TL1A-DR3 Interactions Research Articles

Role of the TNF-family cytokine TL1A and its receptor DR3 in systemic autoimmunity and glomerulonephritis

Abstract DR3 (Tnsfrsf25) is a death domain-containing tumor necrosis factor receptor found primarily on activated T cells and innate lymphocytes. Interaction with its ligand the TNF-family cytokine TL1A plays critical roles in diverse autoimmune disease models in facilitating T cell accumulation at the site of inflammation while the systemic response was unaffected. To determine whether DR3 could play a role in systemic autoimmunity, we studied the role of DR3 in the MLR/lpr mouse model of lupus. Lpr mice have a mutation in the TNF family receptor Fas (CD95, Tnfrsf6) that impair its expression, causing a systemic autoimmune disease that mimics systemic lupus erythematosus (SLE) observed in humans. DR3 deficient lpr mice developed identical degrees of lymphadenopathy, splenomegaly compared to control littermates. Accumulation of autoantibodies was also not dependent on DR3. However, DR3 deficiency significantly protected MRL/lpr mice from IgG and C3 glomerular immune complex deposition and DR3 deficient kidneys had decreased medullary T cell accumulation, decreased periglomerular and medullary macrophage infiltrates, reduced proteinuria and reduced renal pathology. In addition, DR3-deficient CD4+ T cell transfer in a chronic graft-versus-host disease (GVHD) model showed similar levels of autoantibodies and immunoglobulin class switching than with wild-type CD4+ T cells but decreased proteinuria and reduced renal pathology. These findings show that DR3 specifically promotes renal pathology in the MRL/lpr mouse model of lupus nephritis and in chronic GVHD without affecting systemic autoimmunity. Blockade of TL1A-DR3 interactions may be a novel strategy to counter nephritis and other organ damage in human SLE.

Soluble TL1A is sufficient for activation of death receptor 3.

Death receptor 3 (DR3) is a typical member of the tumor necrosis factor receptor family, and was initially identified as a T-cell co-stimulatory molecule. However, further studies revealed a more complex and partly dichotomous role for DR3 and its ligand TL1A under (patho)physiological conditions. TL1A and DR3 are not only a driving force in the development of autoimmune and inflammatory diseases, but also play an important role in counteracting these processes through an increase in the number of regulatory T cells. Ligands of the tumor necrosis factor family typically occur in two forms, membrane-bound and soluble, that can differ strikingly with respect to their efficacy in activating their corresponding receptor(s). Ligand-based approaches to activate the TL1A-DR3 pathway therefore require understanding of the molecular prerequisites of TL1A-based DR3 activation. To date, this has not been addressed. Here, we show that recombinant soluble trimeric TL1A is fully sufficient to strongly activate DR3-associated pro- and anti-apoptotic signaling pathways. In contrast to the TRAIL death receptors, which are much better activated by soluble TRAIL upon secondary ligand oligomerization, but similarly to the death receptor tumor necrosis factor receptor 1, DR3 is efficiently activated by soluble TL1A trimers. Additionally, we have measured the affinity of TL1A-DR3 interaction in a cell-based system, and demonstrated TL1A-induced DR3 internalization. Identification of DR3 as a tumor necrosis factor receptor that responds to soluble ligand trimers without further oligomerization provides a basis for therapeutic exploitation of the TL1A-DR3 pathway.

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 (HYP2P.333)

Abstract The TNF-family cytokine TL1A (Tnfsf15) costimulates T cells and type 2 innate lymphocytes (ILC2) through its receptor DR3 (Tnfrsf25). DR3-deficient mice have reduced T cell accumulation at the site of inflammation, and reduced ILC2-dependent immune responses in a number of models of autoimmune and allergic diseases. In allergic lung disease models, immunopathology and local Th2 and ILC2 accumulation is reduced in DR3 deficient mice despite normal systemic priming of Th2 responses and generation of T cells secreting IL-13 and IL-4, prompting the question of whether TL1A promotes the development of other T cell subsets that secrete cytokines to drive allergic disease. Here we find that TL1A potently promotes generation of murine T cells producing IL-9 (Th9) by signaling through DR3 in a cell-intrinsic manner. TL1A enhances Th9 differentiation through an IL-2 and STAT5-dependent mechanism, unlike the TNF-family member OX40, which promotes Th9 through IL-4 and STAT6. Th9 differentiated in the presence of TL1A are more pathogenic, and endogenous TL1A signaling through DR3 on T cells is required for maximal pathology and IL-9 production in allergic lung inflammation. Taken together, these data identify TL1A-DR3 interactions as a novel pathway that promotes Th9 differentiation and pathogenicity. TL1A may be a potential therapeutic target in diseases dependent on IL-9.

The TNF-family cytokine receptor death-receptor 3 (TNFRSF25) is required for nephritis but not systemic autoimmunity in the lpr murine model of lupus (CCR5P.209)

Abstract DR3 (Tnfrsf25) is a death domain-containing tumor necrosis factor receptor found primarily on activated T cells and innate lymphocytes. Interaction with its ligand, the TNF-family cytokine TL1A, plays a critical role in diverse autoimmune disease models in facilitating T cell accumulation at the site of inflammation while not affecting the systemic response. To determine whether DR3 could play a role in systemic autoimmunity, we studied the role of DR3 in the MRL/lpr mouse model of lupus. Lpr mice have a mutation in the TNF family receptor Fas (CD95, Tnfrsf6) that impairs its expression, causing systemic autoimmune disease that mimics systemic lupus erythematosus (SLE) observed in humans. DR3 deficient lpr mice developed identical degrees of lymphadenopathy, splenomegaly and double-negative T cells compared to control littermates. Expansion of effector T and B cell subsets were also not dependent on DR3. However, DR3 deficiency significantly protected MRL/lpr mice from IgG and C3 glomerular immune complex deposition and DR3 deficient kidneys had decreased medullary T cell accumulation, decreased periglomerular and medullary macrophage infiltrates and reduced proteinuria. These findings show that DR3 specifically promotes renal pathology in the MRL/lpr mouse model of lupus nephritis without affecting systemic autoimmunity or other features of Fas deficiency. Blockade of TL1A-DR3 interactions may be a novel strategy to counter nephritis and other organ damage in human SLE.

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.

The TNF family cytokine TL1A (Tnfsf15) costimulates T cells and type 2 innate lymphocytes (ILC2) through its receptor DR3 (Tnfrsf25). DR3-deficient mice have reduced T cell accumulation at the site of inflammation and reduced ILC2-dependent immune responses in a number of models of autoimmune and allergic diseases. In allergic lung disease models, immunopathology and local Th2 and ILC2 accumulation is reduced in DR3-deficient mice despite normal systemic priming of Th2 responses and generation of T cells secreting IL-13 and IL-4, prompting the question of whether TL1A promotes the development of other T cell subsets that secrete cytokines to drive allergic disease. In this study, we find that TL1A potently promotes generation of murine T cells producing IL-9 (Th9) by signaling through DR3 in a cell-intrinsic manner. TL1A enhances Th9 differentiation through an IL-2 and STAT5-dependent mechanism, unlike the TNF-family member OX40, which promotes Th9 through IL-4 and STAT6. Th9 differentiated in the presence of TL1A are more pathogenic, and endogenous TL1A signaling through DR3 on T cells is required for maximal pathology and IL-9 production in allergic lung inflammation. Taken together, these data identify TL1A-DR3 interactions as a novel pathway that promotes Th9 differentiation and pathogenicity. TL1A may be a potential therapeutic target in diseases dependent on IL-9.

180 : The TNF family member TL1A: A key player in type 2 immunity in both adaptive and innate lymphocytes

The TNF-family cytokine TL1A costimulates T cells through its receptor DR3. TL1A polymorphisms and increased TL1A expression has been linked to Rheumatoid Arthritis and Inflammatory Bowel Disease. TL1A-DR3 interactions are required for diverse mouse models of autoimmune disease. The effects of TL1A on T cell differentiation and its role in innate lymphocyte biology has not been explored. During T cell activation, we have found that TL1A costimulation specifically promotes production of the allergy-promoting cytokine IL-9 through a mechanism dependent on IL-2 and STAT5 signaling, and TL1A promotes pathology in mouse models of asthma and ocular inflammation. Transgenic mice chronically expressing TL1A spontaneously develop small intestinal pathology characterized by high levels of IL-13, muscular and goblet cell hyperplasia, and infiltration with immune cells. These histological changes are dependent on IL-13 but not T cells or commensal flora. We find that the major IL-13 producing cells in TL1A transgenic mice lack T and B cell lineage markers and are phenotypically similar to ‘type 2’ innate lymphocytes (ILC2), which promote allergic and anti-parasitic responses in mice. ILC2 express surface DR3 and produce IL-13 in response to TL1A ex vivo. However, ILC2 can be expanded normally in DR3 deficient mice by IL-25 or IL-33, or Nippostrongylus brasiliensis, and DR3 deficient mice clear Nippostrongylus normally from the intestine. TL1A can thus induce IL-13 production by innate lymphocytes through mechanisms distinct from parasitic infection. Taken together, these data demonstrate that TL1A coordinately enhances type 2 immunity in both innate and adaptive lymphocytes and may be a good target for therapy in allergic diseases.

Sustained TL1A(TNFSF15)expression on both lymphoid and myeloid cells leads to mild spontaneous intestinal inflammation and fibrosis

TL1A is a member of the TNF superfamily, and its expression is increased in the mucosa of inflammatory bowel disease patients. Moreover, patients with certain TNFSF15 variants over-express TL1A and have a higher risk of developing strictures in the small intestine. Consistently, mice with sustained Tl1a expression in either lymphoid or myeloid cells develop spontaneous ileitis and increased intestinal collagen deposition. Transgenic (Tg) mice with constitutive Tl1a expression in both lymphoid and myeloid cells were generated to assess their in vivo consequence. Constitutive expression of Tl1a in both lymphoid and myeloid cells showed increased spontaneous ileitis and collagen deposition than WT mice. T cells with constitutive expression of Tl1a in both lymphoid and myeloid cells were found to have a more activated phenotype, increased gut homing marker CCR9 expression, and enhanced Th1 and Th17 cytokine activity than WT mice. Although no differences in T cell activation marker, Th1 or Th17 cytokine activity, ileitis, or collagen deposition were found between constitutive Tl1a expression in lymphoid only, myeloid only, or combined lymphoid and myeloid cells. Double hemizygous Tl1a-Tg mice appeared to have worsened ileitis and intestinal fibrosis. Our findings confirm that TL1A-DR3 interaction is involved in T cell-dependent ileitis and fibrosis.

The Role of TL1A and DR3 in Autoimmune and Inflammatory Diseases

TNF-like ligand 1A (TL1A), which binds its cognate receptor DR3 and the decoy receptor DcR3, is an identified member of the TNF superfamily. TL1A exerts pleiotropic effects on cell proliferation, activation, and differentiation of immune cells, including helper T cells and regulatory T cells. TL1A and its two receptors expression is increased in both serum and inflamed tissues in autoimmune diseases such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and ankylosing spondylitis (AS). Polymorphisms of the TNFSF15 gene that encodes TL1A are associated with the pathogenesis of irritable bowel syndrome, leprosy, and autoimmune diseases, including IBD, AS, and primary biliary cirrhosis (PBC). In mice, blocking of TL1A-DR3 interaction by either antagonistic antibodies or deletion of the DR3 gene attenuates the severity of multiple autoimmune diseases, whereas sustained TL1A expression on T cells or dendritic cells induces IL-13-dependent small intestinal inflammation. This suggests that modulation of TL1A-DR3 interaction may be a potential therapeutic target in several autoimmune diseases, including IBD, RA, AS, and PBC.

Expression of DcR3 and Its Effects in Kaposi’s Sarcoma-Associated Herpesvirus-Infected Human Endothelial Cells

Objective: Kaposi’s sarcoma-associated herpesvirus (KSHV) is classified as a gamma-herpesvirus and it causes Kaposi’s sarcoma in patients infected with the human immunodeficiency virus (HIV). Decoy receptor 3 (DcR3) is known as a decoy receptor for Fas ligand, LIGHT and TL1A and it can neutralize the biological effect of TL1A by inhibiting the TL1A-DR3 interaction in human endothelial cells. The present study examined the expression of DcR3 in human endothelial cells and its effect during the early stages of KSHV infection. Methods: The expression of DcR3 was assessed using real-time RT-PCR and ELISA in human umbilical cord vein endothelial cells (HUVECs) infected with KSHV. Cell proliferation and apoptosis of KSHV-infected HUVECs were assessed after treatment of infected cells with an anti-DcR3 antibody or recombinant human TL1A. Results: DcR3 expression was induced during the early phase of KSHV infection. Inhibition of DcR3 with anti-DcR3 antibodies or recombinant human TL1A-induced apoptosis in KSHV-infected HUVECs. Conclusion: The expression of DcR3 plays an important role in the prevention of apoptosis in HUVECs during the early phases of KSHV infection, thus ensuring the successful establishment and maintenance of the viral infection.

The TNF-family cytokine TL1A drives IL-13-dependent small intestinal inflammation.

The tumor necrosis factor (TNF)-family cytokine TL1A (TNFSF15) costimulates T cells through its receptor DR3 (TNFRSF25) and is required for autoimmune pathology driven by diverse T-cell subsets. TL1A has been linked to human inflammatory bowel disease (IBD), but its pathogenic role is not known. We generated transgenic mice that constitutively express TL1A in T cells or dendritic cells. These mice spontaneously develop IL-13-dependent inflammatory small bowel pathology that strikingly resembles the intestinal response to nematode infections. These changes were dependent on the presence of a polyclonal T-cell receptor (TCR) repertoire, suggesting that they are driven by components in the intestinal flora. Forkhead box P3 (FoxP3)-positive regulatory T cells (Tregs) were present in increased numbers despite the fact that TL1A suppresses the generation of inducible Tregs. Finally, blocking TL1A-DR3 interactions abrogates 2,4,6 trinitrobenzenesulfonic acid (TNBS) colitis, indicating that these interactions influence other causes of intestinal inflammation as well. These results establish a novel link between TL1A and interleukin 13 (IL-13) responses that results in small intestinal inflammation, and also establish that TL1A-DR3 interactions are necessary and sufficient for T cell-dependent IBD.

The TNF-family cytokine TL1A drives IL-13-dependent small intestinal inflammation.

The TNF family cytokine TL1A (TNFSF15) costimulates T cells through its receptor DR3 (TNFRSF25) and is required for autoimmune pathology driven by diverse T cell subsets. TL1A has been linked to human inflammatory bowel disease (IBD), but its pathogenic role is not known. We generated transgenic mice that constitutively express TL1A in T cells or dendritic cells. These mice spontaneously develop IL-13 dependent inflammatory small bowel pathology that strikingly resembles the intestinal response to nematode infections. These changes were dependent on the presence of a polyclonal TCR repertoire, suggesting that they are driven by components in the intestinal flora. FoxP3+ Treg were present in increased numbers despite the fact that TL1A suppresses the generation of inducible Treg. Finally, blocking TL1A-DR3 interactions abrogates TNBS-colitis, indicating that these interactions influence other causes of intestinal inflammation as well. These results establish a novel link between TL1A and IL-13 responses that results in small intestinal inflammation and establish that TL1A-DR3 interactions are necessary and sufficient for T cell-dependent IBD.

TL1A-DR3 Interactions are Important in Both Adaptive and Innate Immunity in Inflammatory Arthritis

TL1A-DR3 Interactions are Important in Both Adaptive and Innate Immunity in Inflammatory Arthritis

T.80. TL1A-DR3 Interactions in T-cell Mediated Autoimmunity; an Attractive Target for Immunotherapy

T.80. TL1A-DR3 Interactions in T-cell Mediated Autoimmunity; an Attractive Target for Immunotherapy

41 TL1A-DR3 interactions drive immunopathology mediated by multiple T-cell subsets

41 TL1A-DR3 interactions drive immunopathology mediated by multiple T-cell subsets

The TNF-Family Receptor DR3 is Essential for Diverse T Cell-Mediated Inflammatory Diseases

DR3 (TRAMP, LARD, WSL-1, TNFRSF25) is a death-domain-containing tumor necrosis factor (TNF)-family receptor primarily expressed on T cells. TL1A, the TNF-family ligand for DR3, can costimulate T cells, but the physiological function of TL1A-DR3 interactions in immune responses is not known. Using DR3-deficient mice, we identified DR3 as the receptor responsible for TL1A-induced T cell costimulation and dendritic cells as the likely source for TL1A during T cell activation. Despite its role in costimulation, DR3 was not required for in vivo T cell priming, for polarization into T helper 1 (Th1), Th2, or Th17 effector cell subtypes, or for effective control of infection with Toxoplasma gondii. Instead, DR3 expression was required on T cells for immunopathology, local T cell accumulation, and cytokine production in Experimental Autoimmune Encephalomyelitis (EAE) and allergic lung inflammation, disease models that depend on distinct effector T cell subsets. DR3 could be an attractive therapeutic target for T cell-mediated autoimmune and allergic diseases.

TL1A–DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease

T helper type 17 (Th17) cells play an important pathogenic function in autoimmune diseases; their regulation, however, is not well understood. We show that the expression of a tumor necrosis factor receptor family member, death receptor 3 (DR3; also known as TNFRSF25), is selectively elevated in Th17 cells, and that TL1A, its cognate ligand, can promote the proliferation of effector Th17 cells. To further investigate the role of the TL1A–DR3 pathway in Th17 regulation, we generated a TL1A-deficient mouse and found that TL1A−/− dendritic cells exhibited a reduced capacity in supporting Th17 differentiation and proliferation. Consistent with these data, TL1A−/− animals displayed decreased clinical severity in experimental autoimmune encephalomyelitis (EAE). Finally, we demonstrated that during EAE disease progression, TL1A was required for the optimal differentiation as well as effector function of Th17 cells. These observations thus establish an important role of the TL1A–DR3 pathway in promoting Th17 cell function and Th17-mediated autoimmune disease.

TL1A-induced NF-κB Activation and c-IAP2 Production Prevent DR3-mediated Apoptosis in TF-1 Cells

We recently identified TL1A, an endothelium-derived T cell costimulator and a ligand for tumor necrosis factor receptor superfamily members DR3 and decoy receptor 3. To elucidate the signaling events triggered by TL1A-DR3 interaction and to understand the molecular mechanisms regulating DR3-mediated apoptosis, we have studied the effect of TL1A and an agonistic DR3 monoclonal antibody in human erythroleukemic TF-1 cells, which express DR3 endogenously. TL1A induced the formation of a DR3 signaling complex containing TRADD, TRAF2, and RIP and activated the NF-kappaB and the ERK, JNK, and p38 mitogen-activated protein kinase pathways. However, TL1A or an agonistic DR3 monoclonal antibody did not induce apoptosis in these cells nor were there detectable levels of FADD or procaspase-8 seen in the signaling complex. Interestingly, DR3-mediated apoptosis was induced in TF-1 cells in the presence of a NF-kappaB pathway-specific inhibitor but not in the presence of mitogen-activated protein kinase inhibitors, either alone or in combination, suggesting that DR3-induced NF-kappaB activation was responsible for resistance to apoptosis in these cells. Consistent with this, we found that TL1A significantly increased the production of c-IAP2, a known NF-kappaB-dependent anti-apoptotic protein, and that the NF-kappaB inhibitor or cycloheximide prevented its synthesis. Furthermore, inhibition of c-IAP2 production by RNA interference significantly sensitized TF-1 cells to TL1A-induced apoptosis. Our study identifies a molecular mechanism by which TL1A and DR3 regulate cell fate in TF-1 cells.