Introduction

Tumor Necrosis Factor (TNF) and TNF-receptor superfamilies, TNFSF and TNFRSF, respectively, include a wide array of proteins with pivotal roles in the development and function of the immune system.¹ Tumor Necrosis Factor (TNF)-like cytokine 1A (TL1A) is encoded by the TNFSF15 gene and was first described in 2002 as an endothelial factor expressed in response to TNF and Interleukin (IL)-1α stimulation.² Since then, its expression has been recognized in Antigen Presenting Cells (APCs), T-cells and non-immune cells and its corresponding pathways are linked to diverse effects on immune regulation, autoimmunity and fibrosis.³

TL1A is primarily found as a type II transmembrane protein that forms stable homotrimers.⁴ A soluble form of TL1A is generated after proteolytic cleavage by TNF-α-converting enzyme (TACE).⁴ Functional signaling is dependent upon binding to death-domain receptor 3 (DR3), while TL1A also binds to soluble Decoy Receptor 3 (DcR3), which antagonizes DR3 for ligand binding, thus, preventing downstream signaling.² The TL1A/DR3/DcR3 system has been extensively studied in Inflammatory Bowel Disease (IBD) and was shown to play a crucial and multifaceted role in the regulation of mucosal homeostasis, but also actively contribute to intestinal inflammation and fibrosis.¹ Anti-TL1A monoclonal antibodies are emerging novel agents for the treatment of autoimmune diseases. Most of the data stem from early clinical trials in IBD, where their safety and tolerance have been demonstrated, with largely promising results regarding clinical efficacy.⁵ Similarly, a growing body of evidence, implicating the TL1A/DR3/DcR3 system in other inflammatory conditions, indicates the potential of modification of this pathway as a therapeutic means for those diseases.^6–8

In this narrative review, we will summarize the main downstream effects of TL1A/DR3 signaling with focus on their relevance to chronic inflammatory conditions. We will also provide experimental data and mechanistic evidence from animal models that link TL1A to the pathogenesis of IBD but also extraintestinal inflammation. Most importantly, in the light of accumulating clinical data on anti-TL1A antibodies, we will speculate on the therapeutic potential of blocking the TL1A/DR3 pathway in chronic immune mediated conditions and review data from the first studies that evaluated the clinical use of anti-TL1A monoclonal antibodies.

Immunobiology of the TL1A/DR3/DcR3 System

Structure and Signaling

TL1A was initially reported for its expression in endothelial cells, more precisely in umbilical vein endothelial cells (HUVEC).² Since then, regulation of TL1A expression has been identified in monocytes/macrophages and dendritic cells (DCs) in response to Toll-like Receptor (TLR) ligands, Fc gamma region activation, lipopolysaccharides and bacterial stimulation.^9–12 Additionally, T-cells express TL1A after T-cell receptor (TCR) stimulation.¹³

DR3 (TNFRSF25) is a type I transmembrane protein with a cytoplasmic domain which features a death domain (DD) that is associated with downstream signaling.² DR3, like TL1A, forms a trimer and, presently, its only known ligand is TL1A. Among members of the TNSFR family, DR3 exhibits the highest homology with TNFR1, especially in their DD domains.¹⁴ Several splice variants of DR3 have been recognized, with recent literature suggesting potential links to immune-mediated conditions.¹⁵ Those variants have been reported in both humans and mice and linked to diverse functionality, which derives from the fact that they may translate into transmembrane or purely soluble DR3 protein isoforms.^16,17 DR3 is constitutively expressed in the lymphoid lineage, including CD4+ and CD8+ T-cells, NK cells, B-cells, and plasma cells, as well as innate lymphoid cells (ILCs).¹⁸ Accordingly, DR3 expression is abundant in lymphocyte rich tissues including the spleen, intestine, and lung.¹⁸ Intriguingly, DR3 expression in intestinal epithelial cells seems to be an important factor preventing intestinal injury and increased intestinal permeability,¹⁹ while DR3 expression by intestinal and lung fibroblasts indicate its potential implication in fibrosis.²⁰

Both transmembrane and soluble TL1A binding to DR3 and ΤL1A/DR3 ligation exerts either pro-inflammatory/proliferative or pro-apoptotic effects on T-cells.² Interestingly, soluble TL1A binding to DR3 favours pro-inflammatory responses.²¹ In fact, diverse immunological functions have been attributed to the transmembrane and soluble TL1A with the latter demonstrating more pronounced inflammatory effects, while cell-type specific TL1A cleavage differences allow for cell-type specific bioavailability of sTL1A.²² The DD domain of the DR3 receptor plays a key role in TL1A/DR3 downstream signaling. After their binding, TNF receptor 1-associated protein (TRADD) is recruited, and binds to DR3 through a DD:DD interaction.²³ Separate pathways are activated to trigger the pro-inflammatory and the pro-apoptotic effects that the TL1A/DR3 binding exerts.

In reference to the molecular pathways involved in pro-inflammatory TL1A/DR3 responses, TNF receptor associated factor 2 (TRAF2) and receptor-interacting serine/threonine-protein kinase 1 (RIPK1) are employed.²⁴ Following polyubiquitination, RIPK1 recruits the mitogen activated protein kinases (MAPKs), phosphoinositide 3-kinase (PI3K) and the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factor, leading to its translocation to the nucleus and the transcriptional upregulation of pro-inflammatory genes.²⁵ In contrast an alternative signaling pathway mediated the pro-apoptotic effects of TL1A/DR3 binding. More specifically, TRADD binds to the Fas-associated death domain (FADD) and the RIPK3, which leads to the activation of the caspase-8-containing death-inducing signaling complex (DISC) and the subsequent caspase-mediated pathway, leading to apoptosis.²⁶ Determination of the dominant downstream pathway remains unclear, although it appears to be dependent upon T-cellular and inflammatory ambient conditions.¹ Regarding the cellular context, TL1A/DR3 pro-inflammatory signaling is promoted in lymphocyte as this pathway appears to be important for their activation.²⁷ In fact, cellular inhibitor of apoptosis protein (c-IAP) is upregulated following NF-κB activation, while absence of the latter promotes apoptotic signals.²⁷

Interestingly, TL1A also binds to its decoy receptor, Decoy Receptor 3 (DcR3, or TNFRSF6B).²⁸ TNFRSF6B does not encode a transmembrane or cytosolic domain, leading to an obligate soluble product.²⁸ DcR3 binds TL1A, and antagonizes its binding to DR3, inhibiting the TL1A/DR3-mediated effects.²⁸ Aside from TL1A, DcR3 also binds to and inhibits downstream processes by Fas ligand (FasL/TNFSF6)²⁹ and LIGHT (TNFSF14).³⁰

The signaling pathways related to the TL1A function are shown in Figure 1, and the structural pleiotropy of the TL1A/DR3/DcR3 system is summarized in Table 1.

Figure 1 TL1A signaling pathway. Tumor Necrosis Factor (TNF)-like cytokine 1A (TL1A, TNFSF15) is primarily found as a type II transmembrane protein (tTL1A) that forms homotrimers, while proteolytic cleavage by TNF-α-converting enzyme (TACE) leads to the production of soluble TL1A (sTL1A). Death-domain receptor 3 (DR3, TNFRSF25) is the main receptor to mediate TL1A effect, and Decoy Receptor 3 (DcR3, TNFSF6B) antagonizes DR3 and exerts a decoy function. Besides its transmembrane form, DR3 is also found in soluble form following alternative splicing. After TL1A/DR3 binding, TNF receptor 1-associated protein (TRADD) is recruited, and binds to DR3 through a DD: DD interaction. Depending on the activated pathways, their binding mediates either pro-inflammatory or pro-apoptotic effects. The proinflammatory pathway includes the recruitment of the TNF receptor associated factor 2 (TRAF2) and receptor-interacting serine/threonine-protein kinase 1 (RIPK1). After polyubiquitination of RIPK1 mitogen activated protein kinases (MAPKs), phosphoinositide 3-kinase (PI3K) and the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factor are recruited leading to the upregulation of pro-inflammatory genes. Alternatively, TRADD binds to the Fas-associated death domain (FADD) and the RIPK3, which leads to the activation of the caspase-8-containing death-inducing signaling complex (DISC) and the subsequent caspase-mediated pathway, leading to apoptosis. Created in BioRender. Kitsou, (K) (2026) https://BioRender.com/xjdw5gq.

Table 1 Structural Pleiotropy of the TL1A/DR3/DcR3 System

Cellular Expression and Function

Innate Immunity

Human monocytes are avid expressors of TL1A, following relevant stimulatory triggers.31 Interestingly, TL1A seems to be an important cytokine bridging innate and adaptive immune responses, as it synergizes with interleukin (IL)-12 and IL-18 to trigger interferon gamma (IFN-γ) production by CD4+ T-cells, as identified in ex vivo experiments using human monocytes.³¹ Autocrine/paracrine TL1A/DR3 interaction in human macrophages has been recognized as a key modulator in the pattern-recognition receptor (PRR)-induced bacterial clearance in human macrophages in the intestine.³² TL1A is produced by human intestinal macrophages, and it is characteristically expressed in Crohn’s disease (CD).⁹ Additionally, TL1A/DR3 binding enhances intestinal defense against pathogens in humans, predominantly bacteria, through the production of reactive oxygen species, nitric oxide synthase 2, and enable autophagy.³² The width of TL1A as a mediator of inflammatory responses in macrophages is underlined by the promotion of foam cell macrophage production in vitro after TL1A treatment and its potential implication in atherosclerosis.³³

Regarding the stimuli that promote TL1A expression, Fc gamma receptor (FcγR) treatment of human monocytes and monocyte-derived DCs in vitro leads to the expression of TL1A and TL1A in monocytes supports T helper 1(Th1) responses.⁹ Intestinal DCs demonstrate upregulation of TL1A transcription following exposure to TLR ligands, lipopolysaccharides and parasitic pathogens, as indicated in a DR3-deficient mouse model.¹³ In the same study, TL1A expression in DCs regulated innate immune responses at the intestine through goblet and Paneth cell function, with its increased expression in CD11c+ DCs leading to their hyperplasia and IL-13 excretion.¹³ Furthermore, recent data suggest increased severity of dextran sulphate sodium (DSS)-colitis in DR3^−/− mice with subsequent impairment of intestinal epithelial cell (IEP) regeneration.¹⁹ Lack of DR3, also, leads to tight junction alterations and increased intestinal permeability.¹⁹

The importance of TL1A/DR3 binding in the lamina propria on the development of intestinal inflammation has been demonstrated by Bamias et al that reported TL1A expression primarily in CD11c^high DCs in the context of murine ileitis.¹⁷ The group also unveiled the synergistic effects of TL1A with IL-12 and IL-18 and with TCR stimulation in the induction of IFN-γ expression in an IL-18-independent manner.¹⁷ Additionally, DSS-induced colitis in TL1A transgenic C57BL/6 mice demonstrates increased inflammatory burden, possibly mediated by the modification of the activation and the migration of DCs.³⁴ In line with this observation, TL1A-mediated effects on DCs is further supported by the regulatory immunological effects of the TL1A/DcR3 binding in splenocytes, where DC differentiation and maturation was assessed along with the subsequent effector T-cell function in mice.³⁵

ILCs are a subset of predominantly tissue-resident T-cells that participate in the regulation of mucosal immunity and adaptive immune responses, while guarding tissue homeostasis.³⁶ DR3/TL1A binding is pivotal for type 2 innate lymphoid cells (ILC2) expansion, survival and function, leading to the activation of this subset and the excretion of IL-5 and IL-13, independent of IL-25 or IL-33 stimulation at mucosal tissues such as the intestine and the lung, as indicated a DR3^−/− mouse model.³⁷ Additionally, TL1A is recognized as an epithelial alarmin in respiratory tissue, both in mice and humans, capable of synergistic effects with IL-33 that favors an IL-9^high immunophenotype in ILC2 with the production of copious amounts of IL-9 in the context of allergic respiratory diseases.³⁸ Regarding ILC3, in vitro data suggest that activation of DR3 signaling leads to proliferation and production of the distinctive cytokine, IL-22, and granulocyte macrophage colony stimulating factor (GM-CSF), an effect amplified by the simultaneous stimulation by IL-23 and IL-1β.^39,40 Furthermore, ILC3 loss and pro-inflammatory effects characterize this phenomenon in intestinal inflammation in mice.⁴⁰

In natural killer (NK) cells, the TL1A/DR3 pathway acts synergistically to IL-12 and IL-18 for the induction of IFN-γ, an effect also manifested in human T-cells.⁴¹ This enhancement of the pro-inflammatory effects of IL-12/IL-18 in the presence of TL1A has been corroborated in intra-epithelial NK cells in mice.⁴² Invariant natural killer T (iNKT) cells are effector innate immune cells generated in thymus. DR3 ligation promotes iNKT-cell effector function by triggering the production of IL-17 in thymic iNKT-cells in mice⁴³ and IL-13 in intestinal iNKT-cells in an allergic lung inflammation mouse model.⁴⁴

Adaptive Immunity

The TL1A/DR3/DcR3 axis regulates mucosal immunity and inflammation mainly through its implications in adaptive immune responses, with abundance of TL1A on APCs and the distribution of DR3 on T-cells. More specifically, among T-cell subsets that express DR3, CD4+ is the dominant population,⁴⁵ including avid expression on Foxp3+ T regulatory cells (Tregs) in mice.⁴⁶ Although TL1A has been studied mostly in relation to CD4+ effector lymphocytes, recent work showed that it may also regulate other lymphocytic subsets. Notably, TL1A knock-out mice show lower counts of TCRγδ+ and CD8+ T-cells in their small intestine, alongside differences in the composition of their intestinal microbiota and the characteristics of adipose tissue, when compared to wild-type mice.⁴⁷ The modification of the microbiota in TL1A knock-out mice was most prominent in the caecum, where a restriction of the abundance of Clostridia and the Firmicutes to Bacteroidetes ratio was found.⁴⁷ The authors hypothesized that this microbiota modification serves as a potentially intermediate step in the regulation of gut inflammation, as increased Firmicutes to Bacteroidetes ratio is correlated to intestinal inflammation in murine models, which has also been corroborated in IBD patients.⁴⁷

In reference to TL1A/DR3 pathways in Treg activation, proliferation and function, DR3 is expressed on Tregs, and TL1A binding promotes their activation and proliferation.³ Among Tregs, this leads to the expansion of both central memory (CD62L^hiCD44+) and effector (CD62L^loCD44+) subsets in secondary lymphoid tissues, as indicated in in vivo experiments in mice.⁴⁸ Strikingly though, TL1A appears to play an inhibitory role in their suppressive function.³ Along the same lines, in SAMP1/YitFc mice with CD-like ileitis, enhancement of DR3 signaling leads to predominance of CD25-FoxP3+, a Treg sub-population lacking proper functionality, and rather represent a reservoir for Treg expansion.^49,50 In contrast, this pro-inflammatory mucosal immunophenotype was reversed after genetic deletion of DR3 with a subsequent CD25+FoxP3+ increase, locally, in the mesenteric lymph nodes accompanied by production of IL-10.⁴⁹ These data indicate a bifunctional role of TL1A/DR3 in the modification of Treg effects, which warrants further investigation. However, based on in vivo data in mice, it is proposed that the level of TL1A stimulation differentially affects the expansion of Tregs as well as their functionality in inhibiting effector subsets.⁵¹ At this point no definitive conclusion can be made regarding the association of TL1A:DR3 with the expansion and function of Tregs, as information has been derived from various animal models. Overall, current knowledge supports the notion that the effect may be variable and dependent on the specific immunological conditions.

In particular, despite a stable low DR3 expression in naïve and resting T-cells,⁵² T-cell activation, leads to significant upregulation of DR3 expression.^18,45 TL1A has been initially considered a Th1 mediator⁵³ since it demonstrates synergistic effects with IL-12 and IL-18 for the enhancement of IFN-γ production in human T-cells.⁴¹ Additionally, it promotes TNF-α expression in isolated human CD4+CD161+ T-cells.⁵⁴ Since those original observations, however, TL1A has been nowadays recognized as the mediator for diverse effector T-cell effects.

Regarding its impact on Th2 responses, most of the available data come from research on inflammatory allergic responses in the lung. In a mouse model of lung inflammation, TL1A/DR3 signaling leads to Th2 polarization and excretion of IL-13 by activated NKT-cells; conversely, antibody blockade of this ligation inhibits these effects.⁴⁴ In addition to airway inflammation, administration of 4C12, a DR3 agonistic antibody, elicits the activation of diverse effector T-cell subsets, including Th1 and Th2, and leads to exacerbation of CD-like ileitis in SAMP1/YitFc mice.⁴⁹ In vivo experiments in transgenic mice that constitutively express TL1A in T-cells and DCs revealed the development of IL-13-driven inflammatory responses in the small intestine resembling those elicited by nematodes, while blocking TL1A/DR3 binding reverses trinitrobenzene sulfonic acid (TNBS)-colitis, a model of CD, with modification of IL-13 and IL-5 expression.⁵⁵ These findings suggest that the Th2 polarization mediated by TL1A/DR3 ligation exerts diverse inflammatory effects in the intestine.

The capacity of TL1A/DR3 to elicit a pro-inflammatory profile in the intestine through Th17 immune effects has been extensively studied.^56–59 Increased expression of TL1A in the APCs of transgenic mice results in the upregulation of the activation markers CD44 and CD69 on CD4+ T-cells within mesenteric lymph nodes and lamina propria, as indicated in a DSS-induced colitis model in TL1A-Transgenic C57BL/6 mice.³⁴ In this context, TL1A promotes the polarization towards Th1 and Th17 immunophenotypes in the lamina propria with increased numbers of CD4+IFN-γ+ and CD4+IL-17A+ cells and increased concentrations of circulating IFN-γ and IL-17A proteins.³⁴ Furthermore, Th17 cells that bear surface DR3 respond to TL1A. The capacity of TL1A/DR3 interaction to promote the CD4+ T-cell polarization towards the Th1, Th17 and Th1/Th17 immunophenotypes has been substantiated by Meng et al, who utilized a DSS-induced colitis model in TL1A knockout mice (TL1A^−/−).⁵³ In the absence of TL1A, DSS-induced colitis led to reduced production of Th1 (IL-12, IFN-γ, TNF-α) and Th17 (IL-23, IL-1β, IL-6, IL-17a) cytokines.⁵³ Most importantly, these changes were accompanied by reduced intestinal inflammation and reduced inflammatory cell infiltration at the lamina propria of TL1A^−/− mice, compared to the control group.⁵³ This observation, taken together with the importance of Th1/Th17 immune dysregulation in IBD, underlines the involvement of TL1A/DR3 in its pathogenesis.⁵³ Similarly, TL1A was shown to enhance the differentiation of Th17 cells and induce the expression of RAR-related orphan receptor c (RORc) mRNA in the supernatant of cells of RA patients, and anti-TNF-α treatment was found to inhibit these outcomes.⁶⁰ However, whether TL1A/DR3 interaction have substantial effects on naïve T-cells remains to be clarified.¹

An additional effector T-cell subset driven by TL1A/DR3 interactions is Th9 cells,^61–63 a multi-cytokine producing CD4+ subset. The initial data recognizing the TL1A Th9-inducing responses were based on observations on the immunological pathogenesis of allergic respiratory inflammation studied in a murine model.⁶⁴ TL1A was found to promote the production of IL-9 and IL-13 in Th9 cells of airway allergy, while TL1A blockade alleviated the allergic phenomena.⁶⁴ Accumulating evidence suggests broader application of this effect, including intestinal inflammation.⁶⁵ In fact, in a DSS-induced colitis model transgenic mice expressing TL1A increased Th9 skewing and production of IL-9, Tissue Growth Factor β (TGF-β) and IL-4 were demonstrated.⁶¹ Translational data from patients with UC suggest a similar immunological pattern.⁶¹ Interestingly, TL1A synergizes with TGF-β and IL-4 in the induction of the Th9 immunophenotype,⁶³ potentially suggesting a positive feedback loop in the development of UC. Finally, Th9 immunophenotype appears to exacerbate intestinal inflammation by compromising the mucosal barrier, as transgenic mice expressing TL1A demonstrated reduced expression of tight junction proteins in response to IL-9 increased expression.⁶² While the correlation between Th9 immunophenotype and UC has been more extensively described, recent data on an experimental model of CD-like ileitis indicate that TL1A/DR3 signaling may also significantly drive Th9 pathogenicity in CD.⁶⁶ In fact, SAMP wild-type mice demonstrate proinflammatory profile compared to DR3^−/−×SAMP knockout mice, with the latter showing more abundant expression of IL-10.⁶⁶ These effects were further validated using RNA sequencing and phophoproteomics where Th9 expression patterns in the experimental colitis model demonstrated similarities to those described in IBD patients.⁶⁶

Taken together, pronounced presence of DR3 in both Tregs and activated T-cells underscores the multifaceted role of the TL1A/DR3/DcR3 system in inflammation and autoimmunity. The cellular and functional pleiotropy of the TL1A/DR3 system is depicted in summary in Figure 2.

Figure 2 Cellular and functional pleiotropy of the TL1A/DR3 system. Monocytes/macrophages, plasma cells, T-cells, dendritic cells and endothelial cells express TL1A, while DR3 is expressed on natural killer (NK) cells, innate lymphoid cells (ILCs), more specifically ILC1 and ILC3, T-cells, including T-helper-1 cells (Th1), Th2, Th9 and Th17, as well as fibroblasts. Created in BioRender. Kitsou, (K) (2026) https://BioRender.com/b33frvh. Abbreviations: IL, interleukin; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; TNF, Tumor Necrosis Factor; TGF, Tissue Growth Factor.

Pre-Clinical Models

Intestinal Inflammation

The link between the TL1A/DR3 axis and IBD has been comprehensively studied and most of the paradigms of its immunological implications and functions are stemming from studies on IBD as cited above. Bamias et al demonstrated the contribution of the TL1A/DR3 signaling in the development of intestinal inflammation in two distinct murine models of CD, where expression of TL1A was detected on CD11c^high DCs and acted synergistically with the IL-12/IL-18 cascade leading to IFN-γ production.17 Other studies have also shown the synergistic effects of TL1A/DR3 signaling in IL-12/IL-18-mediated expression of IFN-γ.^41,67 Additionally, the importance of TL1A for the successful Th1 and Th17 polarization via interactions between DCs and T-cells has been demonstrated in a T-cell transfer colitis model.⁵³ More specifically, transfer of TL1A-deficient CD4+ T-cells failed to enhance colonic inflammation in mice with DSS-induced colitis.⁵³

The effects of TL1A over-expression on T-cells or DCs have been demonstrated in transgenic mice which showed mild small intestine inflammation, alongside marked IL-13 and IL-17 excretion from lamina propria T-cells, goblet cell hyperplasia and impaired immunosuppressive capacity of Tregs.⁵⁵ In another study, DCs from TL1A transgenic mice demonstrated increased expression of costimulatory molecules (CD80 and CD86) and proinflammatory cytokines, and a gut homing signature, indicated by the expression of chemokine receptors including Chemokine Receptor2 (CCR2), CCR5, CCR7, and CX3C motif chemokine receptor 1 (CX3CR1).³⁴ Additionally, the importance of TL1A/DR3 for the maintenance of intact intestinal epithelial barrier has been shown in a DSS-induced colitis model in FMS-TL1A-GFP-transgenic and wild-type mice, whereby overexpression of TL1A was associated with compromised mucosal barrier through interference with tight junction proteins, such as ZO-1, occludin, JAMA, claudin-1, and claudin-3.⁶⁸

As already mentioned, the contribution of TL1A in the pathogenesis of IBD also includes the promotion of Th9 responses. In a DSS-colitis model, TL1A overexpressing mice developed more severe disease as compared to wild type, and this was accompanied by increased generation of Th9 cells and IL-9 production via synergistic effects to lineage development associated TGF-β and IL-4.⁶¹ Furthermore, studies in SAMP1/Yit mice, a model of CD-like small intestinal inflammation validated the implication of TL1:DR3 signaling in Th9 immune responses and strong induction of IL-9, IL-22 and TNF.⁶⁶

Emerging data also suggest that TL1A can be considered an important mediator of fibrosis in IBD. Transgenic mice that overexpress TL1A in lymphoid or myeloid cells develop inflammation in the terminal ileum and enhanced fibrosis both in the small intestine and the colon.⁶⁹ In the same study, DR3 and DcR3 were detected after the stimulation in HT-29 epithelial cell line, indicating TL1A-mediated, epithelial-stromal cell communication. Along the same lines, in vivo data suggest that TL1A overexpressing naïve T-cells were able to induce colitis and fibrostenosis after their transfer to Rag^−/− mice, while Rag^−/−DR3^−/− were protected at least partially from this effect.²⁰ Interestingly, Rag^−/− mice lacking DR3 on fibroblasts were protected from the fibrotic effects of TL1A.²⁰ These effects were recognized through histologic evaluation, measuring the effects of TL1A on the thickness of the colonic and sub-colonic mucosa and the collagen deposition levels in the examined tissue sections.^20,69 Transgenic mice with T-cell lineage specific expression of TL1A (LCK-CD2-TL1A-GFP Tg) demonstrate stimulated collagen production by intestinal fibroblasts compared to their wild-type counterparts in a TNBS-induced experimental colitis model.⁷⁰ This effect was correlated with a TL1A-mediated upregulation of the TGF-β1/Smad3 signaling pathway.⁷⁰

Finally, following challenge with DSS, TL1A-transgenic mice demonstrated increased burden of IBD-like inflammation and fibrosis, and the TGF-β1/p-Smad3 pathway was recognized as the mediator of IL-13 expression and upregulation of the transcriptional paths inducing epithelial to mesenchymal transition.⁷¹ In this context, aggravation of fibrosis was deduced through the detection of increased submucosa thickness and collagen I and III deposition.⁷¹ Administration of anti-TL1A monoclonal antibodies ameliorated those fibrotic effects through a reduction in the number of fibroblasts and myofibroblasts, and reduced collagen synthesis.^71–73 Additionally, in vitro experiments have revealed the pro-fibrotic effects of TL1A as treatment of the human colonic fibroblast CCD-18Co cell line with the peripheral blood mononuclear cell (PBMC) supernatant from healthy donors supplemented with 20 ng/mL TL1A led to cell proliferation and heightened expression of TGF-β1 and p-Smad3.⁷⁰ In ex vivo experiments with cultures of isolated primary intestinal subepithelial myofibroblasts (SEMFs), expression of TL1A mRNA was increased in response to stimulation with IL-1α and TNF-α.⁷⁴

Lung Inflammation

Allergic lung inflammation and atopic predisposition are necessary for the development of asthma and its complications. A compelling body of evidence suggests that TL1A:DR3 signaling is an important mediator of allergic lung inflammation and subsequent airway remodeling. TL1A promotes Th2 polarization and exerts a stimulatory effect on the production of IL-13 by activated NKT-cells.⁴⁴ Administration of anti-TL1A monoclonal antibodies to mice, even days before bronchial stimulation with ovalbumin, attenuated production of IL-5 and IL-13, and lung inflammation.⁴⁴ Similar effects were produced after blockade of DR3.⁴⁴ Similarly, TL1A/DR3 ligation on ILC2 cells, promotes allergic lung inflammation via the production of IL-13 and other type 2 cytokines that orchestrate the pathology of asthma. Critically, DR3 is necessary for ILC2 expansion leading to the upregulation of T-cell responses in lung allergy.⁷⁵ TL1A further enhances type 2 inflammatory responses in allergic lung inflammation, with TL1A-mediated IL-9 production being of significant importance.^64,76 Administration of anti-TL1A monoclonal antibodies restricts the production of Th9 cytokines and the allergic manifestations.⁶⁴

In the bronchial epithelial cell-line BEAS-2B, genetic deletion of either TL1A or DR3 was associated with reduced expression of pro-fibrotic proteins, while TL1A induced the expression of TGF-β.⁷⁷ Those effects were validated in vivo from the same group, by demonstrating that TL1A/DR3 signaling promotes inflammation and airway remodeling in an asthma mouse model induced by ovalbumin, while TL1A or DR3 deletion restricted airway remodeling and tissue destruction.⁷⁷ TL1A-mediated secretion of IL-13 from ILC2s regulated the production of mucus and exerted pro-fibrotic effects leading to airway remodeling in a mouse model of lung inflammation after chronic house dust mite exposure. Intriguingly, DR3 genetic deletion or pharmacological blockade of TL1A exerted protective effects regarding mucus production and airway fibrosis.⁷⁸ Similarly, in murine models of allergen- or bleomycin-induced lung inflammation, anti-TL1A monoclonal antibodies and DR3 deletion prevent the development of airway remodeling and fibrosis through the restriction of peribronchial smooth muscle mass increases and lung collagen.⁷⁹

ILC2s are important components of mucosal immunity, particularly for the maintenance of intact mucosal barriers. IL-25 and IL-33 aid ILC2 responses and support the production of IL-5 and IL-13 in allergic lung inflammation.³⁷ Interestingly, TL1A triggers ILC2 activation independently of the presence of IL-25 and IL-33. Accordingly, DR3^−/− mice were unable to elicit successful ILC2 responses in mice after airway challenge with papain.³⁷ Additionally, in another study following induction of allergic lung inflammation in mice, DR3 upregulated expression was reported, while DR3^−/− mice displayed reduced cellular infiltration in the alveolar mucosa alongside reduced goblet cell hyperplasia that is detected in chronic disease.⁸⁰ Finally, TL1A/DR3 signaling is particularly important in the alveolar epithelial barrier integrity, since TL1A knock-out and conditional knock-out mice were vulnerable to increased inflammatory burden in a lipopolysaccharide (LPS)-induced ARDS model and DR3 deletion also led to barrier dysfunction and aggravated pulmonary edema in the same model.⁸¹

Taken together, those data indicate that TL1A/DR3 axis may be a promising target in allergic lung inflammation and effectively prevent its sequalae.

Skin Inflammation

Psoriasis is a chronic inflammatory condition of the skin that is often associated with arthritis.⁵⁶ It is characterized by aberrant keratinocyte proliferation and differentiation, and an IL-17 immunological profile that relates to disease pathogenesis.⁵⁶ In animiquimod (IMQ)-induced psoriasis-like murine model, baseline expression of TL1A was significantly increased in affected mice, whereas administration of TL1A on IMQ-treated skin enhanced the psoriasiform manifestations by increasing local immune infiltration and upregulation of IFN-γ and IL-17.⁷ Administration of anti-TL1A monoclonal antibodies led to amelioration of these effects.⁷ In another study, using the same model, administration of anti-TL1A monoclonal antibodies suppressed the activation of IL-17-producing γδ T-cells (γδT17) in the affected skin; moreover, TL1A exacerbated psoriasiform lesions in wild-type mice, as compared to their γδT17 deficient counterparts.⁵⁶ Pathogenic γδT17 cells demonstrated elevated expression of DR3.⁵⁶ TL1A acted in synergy with IL-23 to induce the expression of IL-22, a significant psoriasis mediator, while this effect was not achieved by IL-23 alone.⁵⁶ These results indicate that TL1A is a promising target for psoriasis treatment, either as monotherapy or in combination with IL-23 blockade.

Joint Inflammation

Rheumatoid Arthritis (RA) is a chronic systemic autoimmune polyarthritis, the main features of which include joint inflammation, synovial tissue involvement, and damage of cartilage and bone surrounding the affected joints. Fibroblast-like synoviocytes (FLSs) located in the synovium appear to be key players in the development of the disease and its complications.⁵⁷ In vitro data from cultured FLSs derived from RA patients revealed that TL1A promotes the expression of IL-6 through activation of NF-κB and JNK pathways, and this leads to the expansion of Th17 lymphocyte pool.⁵⁷ In another study, TL1A promoted the activity of the hedgehog homologue indian hedgehog (IHH) and its cognate receptor Patched 1, 2 in cultures of FLSs derived from RA patients, leading to the modification of chondrocyte growth and differentiation.⁸² Interestingly, TNFR2 antagonists reversed these effects.^57,82 Additionally, in vitro experiments demonstrated that TL1A excretion from human monocytes was induced after treatment with immune complexes derived from the serum of rheumatoid factor (RF) positive RA patients, or with insoluble immune complexes isolated from the synovial fluid from active RA.³¹ Subsequent treatment of the TF-1 cell-line with the monocyte-excreted TL1A produced proinflammatory and apoptotic effects through synergistic action with IL-12 and IL-18 leading to increased IFN-γ expression in CD4+ T-cells.³¹ Furthermore, treatment of peripheral blood mononuclear cells with recombinant human TL1A led to increased expression of IL-17 mRNA and protein.⁸³

The importance of the TL1A/DR3 signaling in the development and persistence of inflammation and bone involvement in RA has also been shown in studies employing murine models of RA. DR3^−/− mice demonstrated diminished clinical manifestations of antigen-induced arthritis (AIA) and most importantly, were spared from bone erosive effects with reduced numbers of osteoclasts recruited in the affected joints.⁸⁴ Conversely, TL1A exacerbated the arthritic manifestations, and increased osteoclastogenesis.⁸⁴ These effects were reversed after the administration of anti-TL1A monoclonal antibodies.⁸⁴ Similarly, in an AIA model, DR3 expression was positively associated with AIA onset, while DR3^−/− mice did not demonstrate cartilage damage and reduced neutrophil joint infiltration and matrix metalloproteinase-9 concentrations.⁸⁵

Similar results were depicted in animal models of collagen induced arthritis (CIA). In particular, in the CIA model in Wistar rats, an anti-TL1A monoclonal antibody was compared to etanercept in a semi-preventative protocol, where drug administration was commenced on day 6 (prior to the development of clinical manifestations) and a therapeutic protocol, where drug administration followed disease onset.⁸⁶ Interestingly, in the semi-preventative model, anti-TL1A monoclonal antibodies demonstrated better results compared to etanercept concerning disease activity and hind paw volume, while anti-TL1A monoclonal antibodies led to improvement across all histopathology criteria used in the study compared to controls.⁸⁶ In the therapeutic model, anti-TL1A monoclonal antibodies retrieved comparable outcomes to those of etanercept administration.⁸⁶ However, these data are described in Conference Proceedings, thus, more details are yet to be published regarding the effects of anti-TL1A monoclonal antibodies compared to etanercept in this animal model.⁸⁶ Similar effects of TL1A blockade in the amelioration of the CIA murine model have been shown in other studies.⁶ Finally, dioscin from dioscorea nipponica was found to be an effective therapy for CIA inducing reduction of bone erosion and synovial inflammation. Interestingly, the therapeutic effect was associated with downregulation of TL1A and DR3 in the lymph nodes and spleen and of TL1A and IL-9 in the serum.⁸⁷ Taken together, these data strongly support the hypothesis that TL1A may be an important immunological mediator that contributes to the pathophysiology of RA.

TL1A/DR3 signaling appears to regulate bone mineral apposition by osteoblasts in an animal model of Ankylosing Spondylitis (AS), potentially explaining the abnormal bone formation in the axial skeleton, as indicated by higher expression of alkaline phosphatase and mineral apposition in cell cultures of osteoprogenitor cells and osteoblasts of DR3 wild-type mice.⁸⁸ In vivo data demonstrated significantly lower mineralization in the thoracic vertebrae in DR3^−/− mice.⁸⁸

Neurological Inflammation

In a murine model of autoimmune encephalomyelitis, TL1A was found to be necessary for the successful differentiation, proliferation and maintenance of the effector properties of Th17 cells, since TL1A^−/− mice demonstrated reduced clinical severity.⁵⁸ In fact, DR3 would be a promising potential therapeutic target for the achievement of amelioration of T-cell accumulation and proinflammatory cytokine production in autoimmune encephalomyelitis and allergic lung inflammation as demonstrated by in vivo data of DR3 deficient mice in experimental autoimmune encephalomyelitis and allergic lung inflammation models.¹³

Systemic Conditions

Sarcoidosis is characterized by the polarization of CD4 + naïve T-cells toward Th1/Th17 phenotypes and the development of a proinflammatory microenvironment that enables formation of granulomas.⁵⁹ The effects of an anti-TL1A monoclonal antibody on the development of granulomas and disease activity have been assessed in a murine model of sarcoidosis.⁵⁹ Anti-TL1A therapy significantly reduced the formation of granulomas and the differentiation toward the Th1/Th17 immunophenotype.⁵⁹ These effects were associated with significant modification of the PI3K/AKT signaling pathway.⁵⁹

TL1A/DR3 signaling has also been studied in relation to the inflammatory component that participates in the pathophysiology of obesity. TL1A^−/− mice that were fed a high fat diet demonstrated reduced fat mass, reduced hepatic steatosis and improved insulin sensitivity as compared to their TL1A-sufficient littermates.⁸⁹ Additionally, inhibition of TL1A expression led to a reduction of the inflammatory burden in the epididymal white adipose tissue in mice, as indicated by reduced of IL-18Ra⁺ type-1 ILCs and γδT-cells infiltration.⁸⁹ TL1A-induced polarization of macrophages toward the M1 phenotype has been implicated in the development of non-alcoholic steatohepatitis in a murine model of the disease.⁹⁰ In fact, overexpression of TL1A in macrophages and Kupffer cells stemming from the bone marrow of TL1A overexpressing mice promote lipid uptake and a proinflammatory profile in murine primary hepatocytes in vitro.⁹⁰

The main results of mechanistic studies on TL1A/DR3 in animal models are summarized in Table 2.

Table 2 Mechanistic Data from Animal Models on the Role of TL1A:DR3 Signaling in Chronic Inflammation and Fibrosis

Human Observations

Inflammatory Bowel Disease

Bamias et al first demonstrated upregulation of TL1A and DR3 transcripts in IBD. TL1A immunolocalization was found in macrophages and CD4+ and CD8+ T-cells in the lamina propria of CD and in plasma cells in UC.91 Since, elevated expression of TL1A in inflamed mucosal lesions IBD have been described by other groups,^92,93 and involved both ileal and colonic lesions in CD patients. TL1A was shown to induce production of pro-inflammatory cytokines, such as IFN-γ, IL-6, and IL-17, from CD4+CD161+ T-cells, an intestinal-specific population isolated from the inflamed mucosa of CD patients.⁵⁴ In another study, TL1A transcriptional upregulation has been associated with induction of IL-17 expression only, in both CD and UC inflamed colon mucosa.⁹⁴ DcR3 expression is increased in the serum and colonic biopsies of patients with UC compared to controls, and its expression demonstrated significant correlation to the presence of disease activity.⁹⁵ In contrast, circulating levels of TL1A were significantly elevated in UC patients irrespective of relapse or remission of the disease compared to controls.⁹⁵ Similar trends are also reported in CD.⁹⁶ Interestingly, differences among affected locations are reported in CD, as DcR3 expression was more abundant in inflamed ileal and colonic regions, while TL1A expression was more pronounced in colon and serum samples of CD patients.⁹⁶

The potential of TL1A as a mediator in fibrosis in CD has been demonstrated by the ability of the supernatants from mucosal cultures of CD to induce TL1A-mediated proinflammatory responses in primary SEMFs in vitro, in contrast to supernatants from healthy controls.⁷⁴ Increased levels of TL1A were reported in intestinal biopsies obtained from IBD patients and the degree of expression was negatively associated with E-cadherin levels, indicating a detrimental effect on the integrity of the epithelial barrier, while positive associations were reported to pro-fibrotic markers, in a cross-sectional study.⁷¹ Furthermore, in a retrospective study, peripheral TL1A expression in CD patients was associated with the induction of small bowel stenosis, intestinal strictures, and increased histological disease activity in ileal and caecal biopsies.⁹⁷

Finally, associations between TNFSF15 polymorphisms and CD risk (rs4263839, rs3810936, rs6478108, rs4979462, rs6478109, rs7848647, and rs7869487), and UC risk (rs3810936, rs6478108 and rs6478109) have been recognized, some of which demonstrate ancestry specificity.⁹⁸ The TNFSF15 genotype was recently found to influence treatment response to anti-TNF agents, underlying the importance of the TL1A/DR3 axis in the severity of the disease and responsiveness.⁹⁹

Asthma

The implication of TL1A/DR3 axis in asthma has been demonstrated. Upregulation of the TNFSF15 gene was detected in airway epithelium of patients with asthma compared to healthy controls.⁷⁷ The protein content of TL1A in bronchial biopsy specimens from asthma patients correlated with collagen deposition and airway wall thickening, while soluble TL1A was detected in sputum and bronchoalveolar lavage fluid.⁷⁷ Significant increases in the number of DR3+ ILC2s were found in the sputum of patients with mild asthma following an inhalation challenge.¹⁰⁰ In vitro data suggest that this increase is mediated by IL-2, IL-33 and thymic stromal lymphopoietin (TSLP), while TL1A increased IL-5 expression, an effect reversed by dexamethasone.¹⁰⁰ Similar increases were also noted for TL1A expression following the challenge, with patients with eosinophilic asthma demonstrating the greatest upregulation.¹⁰⁰ Interestingly, TL1A/DR3 participates in the development of exacerbated ILC2 responses in eosinophilic asthma and has been proposed as a mediator of steroid resistance.^77,100 Despite the available evidence the role of TL1A/DR3 in eosinophilic infiltration and steroid resistance remains unclear.¹⁰¹

Furthermore, recent data suggest that TL1A is expressed in type 1 and 2 alveolar epithelial cells and basal lung cells in both asthmatic and healthy individuals, applying an “alarmin” role to TL1A, similarly to IL-33 and TSL.³⁸ TL1A demonstrates synergistic effects with IL-33 in lung inflammation and has been proposed as an alarmin that induces IL-9^high ILC2s in response to allergens.³⁸ Its synergy to IL-33, may suggest its role as a potential adjuvant treatment for asthma and atopy along with anti-IL33 blockade.³⁸

Four polymorphisms in the TNFSF15 gene have been detected in childhood onset asthma in white British population, namely rs7856856, rs6478106, rs1857335 and rs10117785.¹⁰² More specifically, rs7856856 was associated with low levels of TL1A in serum and this genotype was also detected in Korean populations with childhood onset asthma with markedly reduced levels of TL1A.¹⁰²

Psoriasis

The participation of TL1A in the pathogenesis of psoriasis has been demonstrated in multiple cohort studies. Increased TL1A mRNA expression and protein production was detected in PBMCs of patients with psoriasis.^103,104 Similarly, serum TL1A concentrations were higher in patients as compared to positive controls with atopic dermatitis and those levels decreased after successful treatment with topical tacrolimus and tar in combination with narrow band (NB)- ultraviolet B light (UVB) phototherapy and oral compound glycyrrhizin.¹⁰⁴ In vitro studies using PBMCs from those populations, showed that soluble TL1A acted in synergy with IL-23 for the induction of IL-17.¹⁰⁴ The percentage of DR3-expressing CD8+ and CD14+ PBMCs was elevated in psoriasis patients compared to healthy controls.¹⁰⁵ Following treatment with topical corticosteroids in combination with oral compound glycyrrhizin and NB-UVB, these cell subsets were decreased, while DR3 expression on PBMCs positively correlated to clinical disease activity scores.¹⁰⁵ While DR3 and DcR3 appear to be constitutively expressed in the skin, significant upregulation of both accompanied by upregulation of TL1A expression was found during active psoriasis with localization to keratinocytes, macrophages and cells at the perivascular/endothelial area.¹⁰⁶ The importance of TL1A regulation in skin inflammation is further underlined by its nuclear localization in inflammatory cells at the affected skin areas.¹⁰⁶ Furthermore, risk-associated single nucleotide polymorphisms at the TNFSF15 locus, namely rs6478108 and rs6478109 have been correlated to psoriasis development.^6,107 These data suggest that TL1A is a potential novel target for the treatment of psoriasis.

Rheumatoid Arthritis

The association between the TL1A:DR3 axis and RA is supported by several yet indirect data. Patients with RA have increased levels of soluble TL1A in plasma/serum and synovial fluid as compared to patients with osteoarthritis and healthy controls.⁸³ Elevated levels of TL1A are detected in the plasma/serum of first-degree relatives of RA patients that were anti-cyclic citrullinated peptide (anti-CCP) positive.⁶ As this population is considered prone to developing RA, those findings indicate that soluble TL1A may serve not only as an indicator of active inflammation but also as a biomarker of a high individual-risk status.Additionally to serum and synovial fluid levels of TL1A, DcR3 levels demonstrated the same pattern in RA patients, especially in RF and anti-CCP positive RA.⁸³ Higher concentrations were also detected in the synovial fluid than in the peripheral blood emphasizing the importance of the local inflammatory environment for the upregulation of the ligand:receptor system.⁸³ Strikingly both studies concluded that administration of anti-TNF agents led to the reduction of TL1A levels in all patients that received the treatment, whilst reduction in TL1A concentration after methotrexate administration was only achieved in those with clinical response.^6,83

Patients with RA are at increased risk for the development of atherosclerosis and consequently cardiovascular disease due to their increased inflammatory burden.¹⁰⁸ TL1A system dysregulation is one putative mediator of atherogenesis in this population, as positive associations between TL1A levels in serum of RA patients and atheromatic plaque progression have been detected, while a low TL1A and DcR3 immunophenotype were linked to improved atheromatosis outcomes in carotids and femoral arteries.¹⁰⁸ These results are further supported by in vitro data and animal studies which indicate that TL1A enhances the formation of foam cells a pivotal step in the development of atheromatous lesion.³³

Genotype-phenotype associations further support the importance of TL1A:DR3 in RA. In a case-control study in the Chinese population, the TC and TT + TC genotypes of rs3810936 and rs7848647 polymorphisms of the TNFSF15 gene were associated with reduced risk of RA development.¹⁰⁹ RA patients that were homozygous for the C allele of rs3810936 showed increased disease severity based on their disease activity index, RF concentration and erythrocyte sedimentation rate.¹⁰⁹ Additionally, patients demonstrating the CC genotype of the rs7848647 featured higher expression of TL1A compared to the rest of the genotypes.¹⁰⁹ Notably, a TNFRSF25 (DR3) gene variant has been detected in RA patients, where four single-nucleotide polymorphisms and a 14-nucleotide long deletion at exon 5 and intron 5 lead to the production of a truncated DR3 protein product.¹⁵ This variant does not contain a functional death domain and after forming a heterotrimer with the wildtype protein inhibits its pro-apoptotic effect.¹⁵ This was further validated in in vivo experiments with transgenic mice that over-expressed the human truncated DR3 variant.¹⁵

Other Inflammatory Conditions

In human studies, the TL1A/DR3 signaling pathway has been shown to be of clinical relevance and genetic associations of TNFSF15 gene polymorphisms have been detected in multiple conditions, supporting its potential as a therapeutic target. Increased serum concentrations are reported in anti-TNF naïve patients with AS compared to healthy controls and anti TNF treatment led to TL1A serum levels comparable to those in healthy subjects.⁸ Gut-derived mononuclear phagocytes expressing TL1A (CX3 CR1+CD59+CCR9+TL1A+IL-23+) are increased in the periphery and synovial fluid in AS and they are presumed to perpetuate the proinflammatory phenotype observed in AS through ILC3 expansion.¹¹⁰ Additionally, TNFSF15 gene rs3810936 TT genotype has been identified as high-risk in the Chinese Han population.¹¹¹

TL1A and DcR3 serum levels are also increased in early and late stages of primary biliary cirrhosis (PBC) and these levels appear to be modified in early disease after treatment with ursodeoxycholic acid.¹¹² Local variations throughout the diseased liver have been identified for the TNFSF15 mRNA, with the affected areas demonstrating increased expression while this phenomenon is restricted in healthy sites of the tissue.¹¹² The TNFSF15 rs4979462 polymorphism has been identified as a risk factor for the development of PBC in the Japanese and the Chinese Han populations.¹¹³

Systematic Lupus Erythematosus (SLE) is another inflammatory condition for which associations with TL1A/DR3 system have been described. When compared to controls, newly diagnosed SLE patients show increased plasma concentrations of TL1A that positively correlate with disease activity.¹¹⁴ TheTNFSF15 gene polymorphisms, rs3810936 and rs7848647, have also been correlated with SLE susceptibility.¹¹⁵

TL1A is also considered a significant cytokine in the immunological pathogenesis of systemic sclerosis. Increased TL1A levels are reported in diffuse cutaneous and limited cutaneous systemic sclerosis patients compared to healthy controls, and these levels correlate to disease activity.¹¹⁶ Lung fibrosis is also a major complication of systemic sclerosis and TL1A/DR3 pathway appears to be a significant contributor in the development of fibrosis and airway remodeling.⁷⁹

Studies on pulmonary sarcoidosis have revealed aberrant TL1A/DR3 signaling in this disease.⁵⁹ Increased TL1A and DR3 expression have been detected in T-cells in the respiratory tissues and alveolar macrophages during the active phase of sarcoidosis compared to inactive and healthy controls and TL1A enhances the production of matrix metalloproteinase 9 in alveolar macrophages, thus contributing to the progression of the disease and the development of granulomas.¹¹⁷

Finally, as indicated by animal studies, TL1A/DR3 signaling is associated with obesity and hepatic steatosis. The potential of TL1A as a target in obesity is further indicated by the detection of rs4979453, a non-coding polymorphism adjacent to the TNFSF15 locus, associated with abdominal fat in men.⁸⁹

Figure 3 demonstrates the multitude of clinical manifestations that have been described in the presence of dysregulation of the TL1A/DR3 system. Table 3 summarizes the involvement of TL1A/DR3 system in inflammatory conditions.

Figure 3 Clinical pleiotropy of the TL1A/DR3/DcR3 system. At the translational level TL1A has been described in a multitude of inflammatory conditions, multiple manifestations of which can be attributed to the proinflammatory and profibrotic effects of the TL1A/DR3 signaling. Created in BioRender. Kitsou, (K) (2026) https://BioRender.com/624qyha. Abbreviations: sTL1A, soluble TL1A; BALF, bronchoalveolar lavage fluid; RF, Rheumatoid Factor; Anti-CCP Ab, Anti-cyclic citrullinated peptide antibody; PBMC, peripheral blood mononuclear cell; UC, Ulcerative Colitis; CD, Crohn’s Disease.

Table 3 Upregulation of TL1A, DR3 and DcR3 in Multiple Inflammatory Conditions

Clinical Data

The multifaceted involvement of TL1A in chronic inflammation led to the development of several different neutralizing anti-TL1A monoclonal antibodies. These agents are being tested not only in IBD, but also in other immune-mediated diseases, namely rheumatoid arthritis, axial spondylarthritis, hidradenitis suppurativa, atopic dermatitis and systemic sclerosis. The completed and ongoing clinical trials of anti-TL1A molecules are presented in Table 4.

Table 4 Completed and Ongoing Clinical Trials of Anti-TL1A Agents

The first antibody that was developed was afimkibart, also known as PF-06480605 and RO7790121. It was well tolerated in healthy individuals when administered at single intravenous (iv) dose of 800mg, 3 consecutive iv doses of 500mg and 3 consecutive subcutaneous (sc) doses of 300mg every other week.118 Later, a singe sc dose of 450mg was tested in a Japanese and a Chinese cohort and found to be well-tolerated too.¹¹⁹ The efficacy of afimkibart in moderate to severe active UC was tested in the open label TUSCANY trial, in which 42 participants were treated with 7 iv doses of 500 mg afimkibart every other week. After treatment, 38.2% reached the primary study endpoint of endoscopic MAYO sub-score of 0 or 1, with respectively promising results of histologic disease activity.⁵ In the TUSCANY-2 trial patients with moderately and severely active UC were treated with 50, 150, 450mg of scafimkibart or placebo every 4 weeks, during the placebo-controlled 12-week induction period.¹²⁴ All participants who completed the induction were then treated with 50, 150 or 450mg of scafimkibart every 4 weeks during the 40-week maintenance period.¹²⁴ At the end of induction, all three treatment arms showed similar results for the primary endpoint of clinical remission defined as total MAYO score less than 3 with no subscore greater than 1 (50mg: 26%, 150mg: 23%, 450mg: 24%) without statistically significant superiority over the placebo arm (12%).¹²⁴ However, in the secondary end-point of clinical remission calculated with the modified MAYO score afimkibart showed superiority over placebo for all three regimens (50mg: 30%, 150mg: 35%, 450mg: 32%, placebo 12%).¹²⁴ Modified Mayo is considered a more subjective tool for the evaluation of disease activity, since it does not include the “Physician’s Global Assessment” component. The adverse and serious adverse events did not differ between the placebo and the treatment groups.¹²⁴ These promising results of TUSCANY and TUSCANY-2 further supported the investigation of afimkibart in UC [Phase 3 trial Ametrine-1 (NCT06589986) and Ametrine-PEDS (NCT07158242)], CD [Phase 2 trial TAHOE (NCT05910528) and Phase 3 trials SIBERITE-1 (NCT06819878) and −2 (NCT06819891)], MASH liver fibrosis (Phase 1, NCT06903065), atopic dermatitis (Phase 2, NCT06863961), and rheumatoid arthritis (Phase 2, NCT07137598).

Tulisokibart, also known as MK-7240 and PRA023, has been tested in patients with CD during the Phase 2a APOLLO-CD trial and in patients with UC during the Phase 2 placebo-controlled ARTEMIS-UC trial. In both trials the participants were treated with 1000mg of iv tulisokibart at day 1, and 500mg iv at week 2, 6 and 10. In the open-label APOLLO-CD, 26% of patients reached the primary end-point of endoscopic improvement.¹²¹ In ARTEMIS-UC two separate cohorts were studied, based on a genetic-based test that predicts the likelihood of response to TL1A blocking, and tulisokibart was found to be superior to placebo for the induction of clinical remission and most of the secondary end-points. In particular, in cohort 1, in which patients were included regardless of their positivity to the predictive test, 26% of tulisokibart-treated patients achieved clinical remission as compared to 1% of the placebo arm. Similarly, among biomarker-positive tested patients, 32% of tulisokibart-treated achieved clinical remission compared to 11% of the placebo arm.¹²⁰ Ongoing placebo-controlled trials of tulisokibart are not confined to IBD, but also include axial spondylarthritis (NCT07133633), hidradenitis suppurativa (NCT06956235), and systemic sclerosis associated with interstitial lung disease (NCT05270668).

It is worth mentioning that a high rate of immunogenicity was reported for afimkibart, while such results were not observed with tulisokibart. Most of the participants of the Phase 1 and TUSCANY trials developed anti-drug-antibodies (82–100%) with lower rates of neutralizing antibodies (10–35%),^5,118,119 while in ARTEMIS-UC this was observed in only 15% of the participants.¹²⁰ The formation of anti-drug- and neutralizing antibodies did not affect the pharmacokinetic and efficacy of afimkibart⁵ and was not correlated with the occurrence of adverse events. However, antibody-positive individuals presented a trend for lower levels of sTL1A, which is representative of lower target engagement.⁵ The significance of antibody formation on afimkibart’s efficacy and adverse event occurrence is expected to be elucidated by the ongoing Phase 3 clinical trials.

Duvakitug, also known as TEV-48574 is being tested in patients with IBD in the Phase 2 RELIEVE UCCD basket trial. The results of the induction trial were recently presented. Participants were treated with placebo or scduvakitug at a single dose of 2250mg followed by either 450mg or 900mg every two weeks. Duvakitug found significantly superior to placebo for the achievement of clinical remission in UC and endoscopic improvement in CD. The higher dose of 900 mg was more effective than 450mg (UC 900mg: 48% [n=22/46], 450mg: 36% [n=17/47], placebo: 20% [n=9/44]; CD 900mg: 48% [n=22/46], 450mg: 26% [n=12/46], placebo: 13%[n=6/46]), and yielded high response rates even in the biologic exposed sub-population (UC:36% [n=5/14], CD: 48% [n=13/27]).^122,123 Duvakitug was also tested in patients with asthma, but the study was terminated for undisclosed reasons.

Two additional anti-TL1A antibodies are under investigation in earlier stages. One Phase 1 trial (NCT06715540) and Phase 2 studies on patients with UC (ULTRAMARINE, NCT07080034) and CD (COMANDOR, NCT07078994) are currently ongoing for the evaluation of BCD-261. Phase 1a/b trial (NCT07029971) on BB-TL1A-VIAL-HLE in healthy individuals and patients with UC is currently recruiting.

Conclusions and Future Perspectives

The strong current evidence on the role of the TL1A/DR3 system as a driver of inflammation in immune-mediated conditions and its implication in the promotion and persistence of fibrosis indicate the merit of exploring its potential as a therapeutic target. TL1A/DR3 signaling has been extensively described in IBD, where clinical trials with anti-TL1A monoclonal antibodies have yielded highly promising preliminary findings. As dysregulation of the TL1A/DR3 pathway appears to be a common denominator of inflammatory responses that take place in various tissues and participate in the pathogenesis not only of IBD but also of other inflammatory and autoimmune diseases, including AS, psoriasis, allergic lung inflammation, targeting TL1A:DR3 signaling could confer multiple therapeutic benefits.

The successful application of TL1A:DR3 therapeutics, however, will be critically dependent upon addressing several questions and challenges that remain unanswered at this moment. Firstly, positioning of anti-TL1A therapies will be difficult to appreciate unless clinicopathological and/or molecular biomarkers become available and allow for selecting patients with defined probabilities of response or failure. Similarly, the potential for administering anti-TL1A mAbs as part of combinatorial regimens, although extremely attractive, should be carefully designed and tested. Secondly, a true effect on reversing established fibrosis has yet to be proven for anti-TL1A treatment and the current clinical trials are not designed to answer this question. Third, the balance between pro-inflammatory and homeostatic functions of the system need to be better understood and also verified in humans. Such approaches should focus on the impact of anti-TL1A administration of the pool of regulatory T-cells, the association with the microbiome and the function of ILCs. Fourth, the interrelation between the functional and decoy receptor for TL1A need to be further delineated, including any clinical implications. Finally, we should be open-minded to the possibility that additional ligands may exist for DR3, a fact that is supported by animal data and may lead to the expectation that anti-DR3 blockade may prove different from anti-TL1A.

Data Sharing Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Author Contributions

Conceptualization: G.B.; Methodology: G.B., K.K. and G.K.; Investigation: K.K., and G.K.; Writing—original draft preparation: K.K.; Writing—review and editing: K.K., G.K., and GB; Visualization: KK, and G.K.; Supervision: G.B.; Project administration: G.B. All authors took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This research received no external funding.

Disclosure

KK and GK report no conflicts of interest in this work. G.B.: Advisor/Lecturer for Janssen, Pfizer, Takeda, Abbvie, MSD, Mylan, Genesis Pharma, Adacyte Therapeutics, Amgen, Ferring, Cooper; Funding (grants/honoraria): Pfizer, Takeda, Abbvie, Aenorasis, BIOCON, BMS; Research/Clinical Trials: Abbvie, Takeda, MSD, Janssen. Personal fees from Abbvie, Adacyte Therapeutics, Amgen, J&J, MSD, Takeda, LILLY and BMS outside the submitted work. The authors report no other conflicts of interest.

References

1. Bamias G, Menghini P, Pizarro TT, Cominelli F. Targeting TL1A and DR3: the new frontier of anti-cytokine therapy in IBD. Gut. 2025;74(4):652–668. doi:10.1136/gutjnl-2024-332504

2. Migone TS, Zhang J, Luo X, et al. TL1A Is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator. Immunity. 2002;16(3):479–492. doi:10.1016/S1074-7613(02)00283-2

3. Taraban V, Slebioda T, Willoughby J, et al. Sustained TL1A expression modulates effector and regulatory T-cell responses and drives intestinal goblet cell hyperplasia. Mucosal Immunol. 2011;4(2):186–196. doi:10.1038/mi.2010.70

4. Weizman T, Levin I, Zaretsky M, Sagi I, Aharoni A. Increased potency of a Bi-specific TL1A-ADAM17 (TACE) inhibitor by cell surface targeting. Front Mol Biosci. 2017;4:61. doi:10.3389/fmolb.2017.00061

5. Danese S, Klopocka M, Scherl EJ, et al. Anti-TL1A antibody PF-06480605 safety and efficacy for ulcerative colitis: a phase 2a single-arm study. Clin Gastroenterol Hepatol. 2021;19(11):2324–2332.e6. doi:10.1016/j.cgh.2021.06.011

6. Song YJ, Choi IA, Meylan F, et al. Circulating TNF-like protein 1A (TL1A) is elevated early in rheumatoid arthritis and depends on TNF. Arthritis Res Ther. 2020;22(1):106. doi:10.1186/s13075-020-02198-9

7. Li L, Fu L, Zhou P, et al. Effects of tumor necrosis factor-like ligand 1A (TL1A) on imiquimod-induced psoriasiform skin inflammation in mice. Arch Dermatol Res. 2020;312(7):481–490. doi:10.1007/s00403-019-02030-8

8. Konsta M, Bamias G, Tektonidou MG, Christopoulos P, Iliopoulos A, Sfikakis PP. Increased levels of soluble TNF-like cytokine 1A in ankylosing spondylitis. Rheumatology. 2013;52(3):448–451. doi:10.1093/rheumatology/kes316

9. Prehn JL, Thomas LS, Landers CJ, Yu QT, Michelsen KS, Targan SR. The T cell costimulator TL1A is induced by FcgammaR signaling in human monocytes and dendritic cells. J Immunol. 2007;178(7):4033–4038. doi:10.4049/jimmunol.178.7.4033

10. Saruta M, Michelsen KS, Thomas LS, Yu QT, Landers CJ, Targan SR. TLR8-mediated activation of human monocytes inhibits TL1A expression. Eur J Immunol. 2009;39(8):2195–2202. doi:10.1002/eji.200939216

11. Endo K, Kinouchi Y, Kakuta Y, Ueki N, Takahashi S, Shimosegawa T. Involvement of NF-kappa B pathway in TL1A gene expression induced by lipopolysaccharide. Cytokine. 2010;49(2):215–220. doi:10.1016/j.cyto.2009.09.006

12. Jacob N, Jacobs JP, Kumagai K, et al. Inflammation independent TL1A-mediated intestinal fibrosis is dependent on the gut microbiome. Mucosal Immunol. 2018;11(5):1466–1476. doi:10.1038/s41385-018-0055-y

13. Meylan F, Davidson TS, Kahle E, et al. The TNF-family receptor DR3 is essential for diverse T cell-mediated inflammatory diseases. Immunity. 2008;29(1):79–89. doi:10.1016/j.immuni.2008.04.021

14. Endres R, Häcker G, Brosch I, Pfeffer K. Apparently normal tumor necrosis factor receptor 1 signaling in the absence of the silencer of death domains. Mol Cell Biol. 2003;23(18):6609–6617. doi:10.1128/MCB.23.18.6609-6617.2003

15. Hashiramoto A, Konishi Y, Murayama K, et al. A variant of death-receptor 3 associated with rheumatoid arthritis interferes with apoptosis-induction of T cell. J Biol Chem. 2018;293(6):1933–1943. doi:10.1074/jbc.M117.798884

16. Screaton GR, Xu XN, Olsen AL, et al. LARD: a new lymphoid-specific death domain containing receptor regulated by alternative pre-mRNA splicing. Proc Natl Acad Sci U S A. 1997;94(9):4615–4619. doi:10.1073/pnas.94.9.4615

17. Bamias G, Mishina M, Nyce M, et al. Role of TL1A and its receptor DR3 in two models of chronic murine ileitis. Proc Natl Acad Sci U S A. 2006;103(22):8441–8446. doi:10.1073/pnas.0510903103

18. Liman N, Lanasa D, Meylan F, Park JH. The ever-expanding role of cytokine receptor DR3 in T cells. Cytokine. 2024;176:156540. doi:10.1016/j.cyto.2024.156540

19. Shimodaira Y, More SK, Hamade H, et al. DR3 regulates intestinal epithelial homeostasis and regeneration after intestinal barrier injury. Cell Mol Gastroenterol Hepatol. 2023;16(1):83–105. doi:10.1016/j.jcmgh.2023.03.008

20. Jacob N, Kumagai K, Abraham JP, et al. Direct signaling of TL1A-DR3 on fibroblasts induces intestinal fibrosis in vivo. Sci Rep. 2020;10(1):18189. doi:10.1038/s41598-020-75168-5

21. Safaya S, Alfarhan M, Sulaiman A, Alsulaiman A, Al-Ali A. TNFSF/TNFRSF cytokine gene expression in sickle cell anemia: up-regulated TNF-like cytokine 1A (TL1A) and its decoy receptor (DcR3) in peripheral blood mononuclear cells and plasma. Cytokine. 2019;123:154744. doi:10.1016/j.cyto.2019.154744

22. Ferdinand JR, Richard AC, Meylan F, Al-Shamkhani A, Siegel RM. Cleavage of TL1A differentially regulates its effects on innate and adaptive immune cells. J Immunol. 2018;200(4):1360–1369. doi:10.4049/jimmunol.1700891

23. Li Z, Yuan W, Lin Z. Functional roles in cell signaling of adaptor protein TRADD from a structural perspective. Comput Struct Biotechnol J. 2020;18:2867–2876. doi:10.1016/j.csbj.2020.10.008

24. Pobezinskaya YL, Choksi S, Morgan MJ, Gang LZ. The adaptor protein TRADD is essential for TL1A/DR3 signaling. J Immunol. 2011;186(9):5212–5216. doi:10.4049/jimmunol.1002374

25. Richard AC, Ferdinand JR, Meylan F, Hayes ET, Gabay O, Siegel RM. The TNF-family cytokine TL1A: from lymphocyte costimulator to disease co-conspirator. J Leukoc Biol. 2015;98(3):333–345. doi:10.1189/jlb.3RI0315-095R

26. Qi C, Wang X, Shen Z, et al. Anti-mitotic chemotherapeutics promote apoptosis through TL1A-activated death receptor 3 in cancer cells. Cell Res. 2018;28(5):544–555. doi:10.1038/s41422-018-0018-6

27. Wen L, Zhuang L, Luo X, Wei P. TL1A-induced NF-κB activation and c-IAP2 production prevent DR3-mediated apoptosis in TF-1 cells*. J Biol Chem. 2003;278(40):39251–39258. doi:10.1074/jbc.M305833200

28. Zhan C, Patskovsky Y, Yan Q, et al. Decoy Strategies: the Structure of TL1A:DcR3 complex. Structure. 2011;19(2):162–171. doi:10.1016/j.str.2010.12.004

29. Weng SC, Wen MC, Hsieh SL, Chen NJ, Tarng DC. Decoy receptor 3 suppresses T-cell priming and promotes apoptosis of effector T-cells in acute cell-mediated rejection: the role of reverse signaling. Front Immunol. 2022;13:879648. doi:10.3389/fimmu.2022.879648

30. Liu W, Zhan C, Cheng H, et al. Mechanistic basis for functional promiscuity in the TNF and TNF receptor superfamilies: structure of the LIGHT:DcR3 assembly. Structure. 2014;22(9):1252–1262. doi:10.1016/j.str.2014.06.013

31. Cassatella MA, Pereira-da-Silva G, Tinazzi I, et al. Soluble TNF-like cytokine (TL1A) production by immune complexes stimulated monocytes in rheumatoid arthritis. J Immunol. 2007;178(11):7325–7333. doi:10.4049/jimmunol.178.11.7325

32. Sun R, Hedl M, Abraham C. TNFSF15 promotes antimicrobial pathways in human macrophages and these are modulated by TNFSF15 disease-risk variants. Cell Mol Gastroenterol Hepatol. 2020;11(1):249–272. doi:10.1016/j.jcmgh.2020.08.003

33. McLaren JE, Calder CJ, McSharry BP, et al. The TNF-like protein 1A–death receptor 3 pathway promotes macrophage foam cell formation in vitro. J Immunol. 2010;184(10):5827–5834. doi:10.4049/jimmunol.0903782

34. Han F, Song J, Jia W, et al. TL1A primed dendritic cells activation exacerbated chronic murine colitis. Life Sci. 2020;262:118220. doi:10.1016/j.lfs.2020.118220

35. Wang YL, Chou FC, Sung HH, et al. Decoy receptor 3 protects non-obese diabetic mice from autoimmune diabetes by regulating dendritic cell maturation and function. Mol Immunol. 2010;47(16):2552–2562. doi:10.1016/j.molimm.2010.07.001

36. Vivier E, Artis D, Colonna M, et al. Innate lymphoid cells: 10 years on. Cell. 2018;174(5):1054–1066. doi:10.1016/j.cell.2018.07.017

37. Yu X, Pappu R, Ramirez-Carrozzi V, et al. TNF superfamily member TL1A elicits type 2 innate lymphoid cells at mucosal barriers. Mucosal Immunol. 2014;7(3):730–740. doi:10.1038/mi.2013.92

38. Schmitt P, Duval A, Camus M, et al. TL1A is an epithelial alarmin that cooperates with IL-33 for initiation of allergic airway inflammation. J Exp Med. 2024;221(6):e20231236. doi:10.1084/jem.20231236

39. Ahn YO, Weeres MA, Neulen ML, et al. Human group3 innate lymphoid cells express DR3 and respond to TL1A with enhanced IL-22 production and IL-2-dependent proliferation. Eur J Immunol. 2015;45(8):2335–2342. doi:10.1002/eji.201445213

40. Li J, Shi W, Sun H, et al. Activation of DR3 signaling causes loss of ILC3s and exacerbates intestinal inflammation. Nat Commun. 2019;10(1):3371. doi:10.1038/s41467-019-11304-8

41. Papadakis KA, Prehn JL, Landers C, et al. TL1A synergizes with IL-12 and IL-18 to enhance IFN-gamma production in human T cells and NK cells. J Immunol. 2004;172(11):7002–7007. doi:10.4049/jimmunol.172.11.7002

42. Tougaard P, Martinsen LO, Zachariassen LF, et al. TL1A aggravates cytokine-induced acute gut inflammation and potentiates infiltration of intraepithelial natural killer cells in mice. Inflamm Bowel Dis. 2019;25(3):510–523. doi:10.1093/ibd/izy351

43. Luo S, Liman N, Li C, et al. The cytokine receptor DR3 identifies and promotes the activation of thymic NKT17 cells. Cell Mol Life Sci. 2023;80(3):76. doi:10.1007/s00018-023-04726-7

44. Fang L, Adkins B, Deyev V, Podack ER. Essential role of TNF receptor superfamily 25 (TNFRSF25) in the development of allergic lung inflammation. J Exp Med. 2008;205(5):1037–1048. doi:10.1084/jem.20072528

45. Twohig JP, Marsden M, Cuff SM, et al. The death receptor 3/TL1A pathway is essential for efficient development of antiviral CD4⁺ and CD8⁺ T-cell immunity. FASEB J. 2012;26(8):3575–3586. doi:10.1096/fj.11-200618

46. Nishikii H, Kim BS, Yokoyama Y, et al. DR3 signaling modulates the function of Foxp3+ regulatory T cells and the severity of acute graft-versus-host disease. Blood. 2016;128(24):2846–2858. doi:10.1182/blood-2016-06-723783

47. Tougaard P, Skov S, Pedersen AE, et al. TL1A regulates TCRγδ+ intraepithelial lymphocytes and gut microbial composition. Eur J Immunol. 2015;45(3):865–875. doi:10.1002/eji.201444528

48. Copsel S, Wolf D, Kale B, et al. Regulatory T cells expanded via TL1A-Ig fusion protein and low dose IL-2 demonstrate potent suppression of graft-versus-host disease. Blood. 2017;130:4434. doi:10.1182/blood.V130.Suppl_1.4434.4434

49. Li Z, Buttó LF, Buela KA, et al. Death receptor 3 signaling controls the balance between regulatory and effector lymphocytes in SAMP1/YitFc mice with crohn’s disease-like ileitis. Front Immunol. 2018;9:362. doi:10.3389/fimmu.2018.00362

50. Zelenay S, Lopes-Carvalho T, Caramalho I, Moraes-Fontes MF, Rebelo M, Demengeot J. Foxp3+ CD25– CD4 T cells constitute a reservoir of committed regulatory cells that regain CD25 expression upon homeostatic expansion. Proc Natl Acad Sci U S A. 2005;102(11):4091–4096. doi:10.1073/pnas.0408679102

51. Sidhu M, Shih D, Targan S. Tregs expressing high Tl1a are proinflammatory and do not protect from T cell induced colitis. (CCR5P.204). J Immunol. 2015;194(1_Supplement):186.6. doi:10.4049/jimmunol.194.Supp.186.6

52. Aiba Y, Nakamura M. The role of TL1A and DR3 in autoimmune and inflammatory diseases. Mediators Inflammation. 2013;2013(1):258164. doi:10.1155/2013/258164

53. Meng F, Jiang X, Wang X, et al. Tumor necrosis factor–like cytokine 1A plays a role in inflammatory bowel disease pathogenesis. Proc Natl Acad Sci U S A. 2023;120(34):e2120771120. doi:10.1073/pnas.2120771120

54. Jin S, Chin J, Seeber S, et al. TL1A/TNFSF15 directly induces proinflammatory cytokines, including TNFα, from CD3+CD161+ T cells to exacerbate gut inflammation. Mucosal Immunol. 2013;6(5):886–899. doi:10.1038/mi.2012.124

55. Meylan F, Song YJ, Fuss I, et al. The TNF-family cytokine TL1A drives IL-13-dependent small intestinal inflammation. Mucosal Immunol. 2011;4(2):172–185. doi:10.1038/mi.2010.67

56. Wang S, Kozai M, Hiraishi M, et al. Roles of tumor necrosis factor-like ligand 1A in γδT-cell activation and psoriasis pathogenesis. Front Immunol. 2024;15:1340467. doi:10.3389/fimmu.2024.1340467

57. Ma Z, Wang B, Wang M, et al. TL1A increased IL-6 production on fibroblast-like synoviocytes by preferentially activating TNF receptor 2 in rheumatoid arthritis. Cytokine. 2016;83:92–98. doi:10.1016/j.cyto.2016.04.005

58. Pappu BP, Borodovsky A, Zheng TS, et al. TL1A–DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease. J Exp Med. 2008;205(5):1049–1062. doi:10.1084/jem.20071364

59. Ma C, Huang J, Zheng Y, et al. Anti-TL1A monoclonal antibody modulates the dysregulation of Th1/Th17 cells and attenuates granuloma formation in sarcoidosis by inhibiting the PI3K/AKT signaling pathway. Int Immunopharmacol. 2024;137:112360. doi:10.1016/j.intimp.2024.112360

60. Zhou M, Liu R, Su D, Feng X, Li X. TL1A increased the differentiation of peripheral Th17 in rheumatoid arthritis. Cytokine. 2014;69(1):125–130. doi:10.1016/j.cyto.2014.04.007

61. Wang D, Li H, Duan YY, et al. TL1A modulates the severity of colitis by promoting Th9 differentiation and IL-9 secretion. Life Sci. 2019;231:116536. doi:10.1016/j.lfs.2019.06.011

62. Zhao C, Wang D, Wu M, et al. Tumor necrosis factor ligand-related molecule 1A affects the intestinal mucosal barrier function by promoting Th9/interleukin-9 expression. J Int Med Res. 2020;48(6):0300060520926011. doi:10.1177/0300060520926011

63. Meylan F, Gomez-Rodriguez J. T cell receptor and co-stimulatory signals for Th9 generation. Methods Mol Biol. 2017;1585:59–71. doi:10.1007/978-1-4939-6877-0_5

64. Niese ML, Pajulas AL, Rostron CR, et al. TL1A priming induces a multi-cytokine Th9 cell phenotype that promotes robust allergic inflammation in murine models of asthma. Mucosal Immunol. 2024;17(4):537–553. doi:10.1016/j.mucimm.2024.03.006

65. Nalleweg N, Chiriac MT, Podstawa E, et al. IL-9 and its receptor are predominantly involved in the pathogenesis of UC. Gut. 2015;64(5):743–755. doi:10.1136/gutjnl-2013-305947

66. Menghini P, Buttó LF, Gomez-Nguyen A, et al. Tumor necrosis factor-like ligand 1a/death receptor 3 signaling regulates the generation of pathogenic T helper 9 cells in experimental crohn’s disease. Gastroenterology. 2025. doi:10.1053/j.gastro.2025.03.035

67. Papadakis KA, Zhu D, Prehn JL, et al. Dominant role for TL1A/DR3 pathway in IL-12 plus IL-18-induced IFN-gamma production by peripheral blood and mucosal CCR9+ T lymphocytes. J Immunol. 2005;174(8):4985–4990. doi:10.4049/jimmunol.174.8.4985

68. Yang M, Jia W, Wang D, et al. Effects and mechanism of constitutive TL1A expression on intestinal mucosal barrier in DSS-induced colitis. Dig Dis Sci. 2019;64(7):1844–1856. doi:10.1007/s10620-019-05580-z

69. Shih DQ, Barrett R, Zhang X, et al. Constitutive TL1A (TNFSF15) expression on lymphoid or myeloid cells leads to mild intestinal inflammation and fibrosis. PLoS One. 2011;6(1):e16090. doi:10.1371/journal.pone.0016090

70. Song J, Sun DL, Li CY, et al. TL1A promotes fibrogenesis in colonic fibroblasts via the TGF-β1/Smad3 signaling pathway. Curr Med Sci. 2024;44(3):519–528. doi:10.1007/s11596-024-2875-1

71. Wenxiu J, Mingyue Y, Fei H, et al. Effect and mechanism of TL1A expression on epithelial-mesenchymal transition during chronic colitis-related intestinal fibrosis. Mediators Inflamm. 2021;2021:5927064. doi:10.1155/2021/5927064

72. Shih DQ, Zheng L, Zhang X, et al. Inhibition of a novel fibrogenic factor Tl1a reverses established colonic fibrosis. Mucosal Immunol. 2014;7(6):1492–1503. doi:10.1038/mi.2014.37

73. Li H, Song J, Niu G, et al. TL1A blocking ameliorates intestinal fibrosis in the T cell transfer model of chronic colitis in mice. Pathol Res Pract. 2018;214(2):217–227. doi:10.1016/j.prp.2017.11.017

74. Bamias G, Filidou E, Goukos D, et al. Crohn’s disease-associated mucosal factors regulate the expression of TNF-like cytokine 1A and its receptors in primary subepithelial intestinal myofibroblasts and intestinal epithelial cells. Transl Res. 2017;180:118–130.e2. doi:10.1016/j.trsl.2016.08.007

75. Meylan F, Hawley ET, Barron L, et al. The TNF-family cytokine TL1A promotes allergic immunopathology through group 2 innate lymphoid cells. Mucosal Immunol. 2014;7(4):958–968. doi:10.1038/mi.2013.114

76. Richard AC, Tan C, Hawley ET, et al. The TNF-family ligand TL1A and its receptor DR3 promote T cell-mediated allergic immunopathology by enhancing differentiation and pathogenicity of IL-9-producing T cells. J Immunol. 2015;194(8):3567–3582. doi:10.4049/jimmunol.1401220

77. Zhang J, Zhang D, Pan Y, et al. The TL1A-DR3 axis in asthma: membrane-bound and secreted TL1A Co-determined the development of airway remodeling. Allergy Asthma Immunol Res. 2022;14(2):233–253. doi:10.4168/aair.2022.14.2.233

78. Steele H, Sachen K, McKnight AJ, Soloff R, Herro R. Targeting TL1A/DR3 signaling offers a therapeutic advantage to neutralizing IL13/IL4Rα in muco-secretory fibrotic disorders. Front Immunol. 2021;12:692127. doi:10.3389/fimmu.2021.692127

79. Herro R, Miki H, Sethi GS, et al. TL1A promotes lung tissue fibrosis and airway remodeling. J Immunol. 2020;205(9):2414–2422. doi:10.4049/jimmunol.2000665

80. Singh RK, Perks WV, Twohig JP, et al. Death Receptor 3 regulates distinct pathological attributes of acute versus chronic murine allergic lung inflammation. Cell Immunol. 2017;320:62–70. doi:10.1016/j.cellimm.2017.09.005

81. Zhang D, Zhang J, Zhang J, et al. Identification of a novel role for TL1A/DR3 deficiency in acute respiratory distress syndrome that exacerbates alveolar epithelial disruption. Respir Res. 2023;24(1):182. doi:10.1186/s12931-023-02488-1

82. Al-Azab M, Wei J, Ouyang X, et al. TL1A mediates fibroblast-like synoviocytes migration and Indian Hedgehog signaling pathway via TNFR2 in patients with rheumatoid arthritis. Eur Cytokine Netw. 2018;29(1):27–35. doi:10.1684/ecn.2018.0405

83. Xiu Z, Shen H, Tian Y, Xia L, Lu J. Serum and synovial fluid levels of tumor necrosis factor-like ligand 1A and decoy receptor 3 in rheumatoid arthritis. Cytokine. 2015;72(2):185–189. doi:10.1016/j.cyto.2014.12.026

84. Bull MJ, Williams AS, Mecklenburgh Z, et al. The death receptor 3–TNF-like protein 1A pathway drives adverse bone pathology in inflammatory arthritis. J Exp Med. 2008;205(11):2457–2464. doi:10.1084/jem.20072378

85. Wang ECY, Newton Z, Hayward OA, et al. Regulation of early cartilage destruction in inflammatory arthritis by death receptor 3. Arthritis Rheumatol. 2014;66(10):2762–2772. doi:10.1002/art.38770

86. Siegel M, Lewis E, Giles D, LaFountaine J, Friedman JR, Spencer A. ABS0150 ANTI-TL1A antibody reduces disease symptoms and pathological changes in rat collagen-induced arthritis. Ann Rheumatic Dis. 2025;84:1940–1941. doi:10.1016/j.ard.2025.06.1486

87. Gao Y, Xia D, You Y, et al. Effects of dioscin from Dioscorea nipponica on TL1A/DR3 and Th9 cells in a collagen-induced arthritis mouse model. Int Immunopharmacol. 2025;147:114028. doi:10.1016/j.intimp.2025.114028

88. Collins FL, Williams JO, Bloom AC, et al. Death receptor 3 (TNFRSF25) increases mineral apposition by osteoblasts and region specific new bone formation in the axial skeleton of male DBA/1 mice. J Immunol Res. 2015;2015:901679. doi:10.1155/2015/901679

89. Tougaard P, Martinsen LO, Lützhøft DO, et al. TL1A regulates adipose-resident innate lymphoid immune responses and enables diet-induced obesity in mice. Int J Obes Lond. 2020;44(5):1062–1074. doi:10.1038/s41366-020-0539-1

90. Luo Y, Guo J, Jia W, et al. TNF-like Ligand 1 aberrance aggravates nonalcoholic steatohepatitis via m1 macrophage polarization. Oxid Med Cell Longev. 2021;2021:3877617. doi:10.1155/2021/3877617

91. Bamias G, Martin C, Marini M, et al. Expression, localization, and functional activity of TL1A, a novel Th1-polarizing cytokine in inflammatory bowel disease. J Immunol. 2003;171(9):4868–4874. doi:10.4049/jimmunol.171.9.4868

92. Prehn JL, Mehdizadeh S, Landers CJ, et al. Potential role for TL1A, the new TNF-family member and potent costimulator of IFN-γ, in mucosal inflammation. Clin Immunol. 2004;112(1):66–77. doi:10.1016/j.clim.2004.02.007

93. Pai YC, Weng LT, Wei SC, et al. Gut microbial transcytosis induced by tumour necrosis factor-like 1A-dependent activation of a myosin light chain kinase splice variant contributes to inflammatory bowel disease. J Crohns Colitis. 2020;15(2):258–272. doi:10.1093/ecco-jcc/jjaa165

94. Ślebioda TJ, Bojarska-Junak A, Stanisławowski M, et al. TL1A as a potential local inducer of IL17A expression in colon mucosa of inflammatory bowel disease patients. Scand J Immunol. 2015;82(4):352–360. doi:10.1111/sji.12324

95. Bamias G, Kaltsa G, Siakavellas SI, et al. High intestinal and systemic levels of decoy receptor 3 (DcR3) and its ligand TL1A in active ulcerative colitis. Clin Immunol. 2010;137(2):242–249. doi:10.1016/j.clim.2010.07.001

96. Bamias G, Kaltsa G, Siakavellas SI, et al. Differential expression of the TL1A/DcR3 system of TNF/TNFR-like proteins in large vs. small intestinal Crohn’s disease. Dig Liver Dis. 2012;44(1):30–36. doi:10.1016/j.dld.2011.09.002

97. Barrett R, Zhang X, Koon HW, et al. Constitutive TL1A expression under colitogenic conditions modulates the severity and location of gut mucosal inflammation and induces fibrostenosis. Am J Pathol. 2012;180(2):636–649. doi:10.1016/j.ajpath.2011.10.026

98. Zhang J, Zhang J, Wu D, Wang J, Dong W. Associations between TNFSF15 polymorphisms and susceptibility to ulcerative colitis and Crohn’s disease: a meta-analysis. Autoimmunity. 2014;47(8):512–518. doi:10.3109/08916934.2014.930735

99. Endo K, Kakuta Y, Moroi R, et al. TL1A (TNFSF15) genotype affects the long-term therapeutic outcomes of anti-TNFα antibodies for Crohn’s disease patients. JGH Open. 2020;4(6):1108–1113. doi:10.1002/jgh3.12398

100. Machida K, Aw M, Salter BMA, et al. The role of the TL1A/DR3 axis in the activation of group 2 innate lymphoid cells in subjects with eosinophilic asthma. Am J Respir Crit Care Med. 2020;202(8):1105–1114. doi:10.1164/rccm.201909-1722OC

101. Skevaki C, Weckmann M, Activation of Group 2 Innate Lymphoid Cells via TL1A/DR3. A Solution to Corticosteroid Resistance? Am J Respir Crit Care Med. 2020;202(8):1067–1069. doi:10.1164/rccm.202007-2658ED

102. Kim KW, Kim DY, Yoon D, et al. Genome-wide association study identifies TNFSF15 associated with childhood asthma. Allergy. 2022;77(1):218–229. doi:10.1111/all.14952

103. Pedersen AE, Schmidt EGW, Sørensen JF, et al. Secretion, blood levels and cutaneous expression of TL1A in psoriasis patients. APMIS. 2015;123(7):547–555. doi:10.1111/apm.12385

104. Li L, Fu L, Lu Y, et al. TNF-like ligand 1A is associated with the pathogenesis of psoriasis vulgaris and contributes to IL-17 production in PBMCs. Arch Dermatol Res. 2014;306(10):927–932. doi:10.1007/s00403-014-1497-z

105. Li L, Lu Y, Fu L, et al. Expression of death receptor 3 (DR3) on peripheral blood mononuclear cells of patients with psoriasis vulgaris. Postgrad Med J. 2018;94(1116):551–555. doi:10.1136/postgradmedj-2018-136040

106. Bamias G, Evangelou K, Vergou T, et al. Upregulation and nuclear localization of TNF-like cytokine 1A (TL1A) and its receptors DR3 and DcR3 in psoriatic skin lesions. Exp Dermatol. 2011;20(9):725–731. doi:10.1111/j.1600-0625.2011.01304.x

107. Képíró L, Széll M, Kovács L, Keszthelyi P, Kemény L, Gyulai R. Genetic risk and protective factors of TNFSF15 gene variants detected using single nucleotide polymorphisms in Hungarians with psoriasis and psoriatic arthritis. Hum Immunol. 2014;75(2):159–162. doi:10.1016/j.humimm.2013.11.006

108. Bamias G, Stamatelopoulos K, Zampeli E, et al. Circulating levels of TNF-like cytokine 1A correlate with the progression of atheromatous lesions in patients with rheumatoid arthritis. Clin Immunol. 2013;147(2):144–150. doi:10.1016/j.clim.2013.03.002

109. Yuan ZC, Wang JM, Su LC, Xu WD, Huang AF. Gene polymorphisms and serum levels of TL1A in patients with rheumatoid arthritis. J Cell Physiol. 2019doi:10.1002/jcp.27834

110. Ciccia F, Guggino G, Zeng M, et al. Proinflammatory CX3CR1+CD59+tumor necrosis factor-like molecule 1A+Interleukin-23+ monocytes are expanded in patients with ankylosing spondylitis and modulate innate lymphoid cell 3 immune functions. Arthritis Rheumatol. 2018;70(12):2003–2013. doi:10.1002/art.40582

111. Wang NG, Wang F, Tan BY, et al. Genetic analysis of TNFST15 variants in ankylosing spondylitis. Int J Clin Exp Pathol. 2015;8(11):15210–15215.

112. Aiba Y, Harada K, Komori A, et al. Systemic and local expression levels of TNF‐like ligand 1A and its decoy receptor 3 are increased in primary biliary cirrhosis. Liver Int. 2014. doi:10.1111/liv.12296

113. Xu WD, Li R, Huang AF. Role of TL1A in inflammatory autoimmune diseases: a comprehensive review. Front Immunol. 2022;13:891328. doi:10.3389/fimmu.2022.891328

114. Xu WD, Chen DJ, Li R, Ren CX, Ye DQ. Elevated plasma levels of TL1A in newly diagnosed systemic lupus erythematosus patients. Rheumatol Int. 2015;35(8):1435–1437. doi:10.1007/s00296-015-3277-2

115. Xu WD, Fu L, Liu XY, et al. Association between TL1A gene polymorphisms and systemic lupus erythematosus in a Chinese Han population. J Cell Physiol. 2019;234(12):22543–22553. doi:10.1002/jcp.28818

116. Xu W, Su L, Qing P, et al. Elevated levels of TL1A are associated with disease activity in patients with systemic sclerosis. Clin Rheumatol. 2017;36(6):1317–1324. doi:10.1007/s10067-017-3612-y

117. Facco M, Cabrelle A, Calabrese F, et al. TL1A/DR3 axis involvement in the inflammatory cytokine network during pulmonary sarcoidosis. Clin Mol Allergy. 2015;13(1):16. doi:10.1186/s12948-015-0022-z

118. Banfield C, Rudin D, Bhattacharya I, et al. First-in-human, randomized dose-escalation study of the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of PF-06480605 in healthy subjects. Br J Clin Pharmacol. 2020;86(4):812–824. doi:10.1111/bcp.14187

119. Fukuhara K, Neelakantan S, Furihata K, et al. Japanese phase 1 study for global development of Anti-TL1A antibody PF-06480605: a randomized, placebo-controlled, single-ascending dose study. Clin Transl Sci. 2025;18(3):e70187. doi:10.1111/cts.70187

120. Sands BE, Feagan BG, Peyrin-Biroulet L, et al. Phase 2 trial of anti-TL1A monoclonal antibody tulisokibart for ulcerative colitis. N Engl J Med. 2024;391(12):1119–1129. doi:10.1056/NEJMoa2314076

121. Feagan BG, Sands BE, Siegel CA, et al. Safety and efficacy of the anti-TL1A monoclonal antibody tulisokibart for Crohn’s disease: a phase 2a induction trial. Lancet Gastroenterol Hepatol. 2025;10(8):715–725. doi:10.1016/S2468-1253(25)00071-8

122. Reinisch W, Stepek D, Kempinski R, et al. OP41 Duvakitug (TEV-48574), an anti-TL1a monoclonal antibody, demonstrates efficacy and favourable safety as an induction treatment in adults with moderately to severely active ulcerative colitis: results from a phase 2b, randomised, double-blind, placebo-controlled, dose-ranging, basket trial (RELIEVE UCCD). J Crohns Colitis. 2025;19(Supplement_1):i79–i80. doi:10.1093/ecco-jcc/jjae190.0039B

123. Jairath V, Kierkus J, Duvall GA, et al. OP40 Duvakitug (TEV-48574), an anti-TL1a monoclonal antibody, demonstrates efficacy and favourable safety as an induction treatment in adults with moderately to severely active Crohn’s disease: results from a phase 2b, randomised, double-blind, placebo-controlled dose-ranging, basket trial (RELIEVE UCCD). J Crohns Colitis. 2025;19(Supplement_1):i77–i78. doi:10.1093/ecco-jcc/jjae190.0039A

124. Danese S, Allegretti JR, Schreiber S, et al. Anti-TL1A antibody, afimkibart, in moderately-to-severely active ulcerative colitis (TUSCANY-2): a multicentre, double-blind, treat-through, multi-dose, randomised, placebo-controlled, phase 2b trial. Lancet Gastroenterol Hepatol. 2025;10(10):882–895. doi:10.1016/S2468-1253(25)00129-3