ABSTRACT
The tumor necrosis factor (TNF)-family cytokine TL1A (TNFSF15) costimulates T cells and promotes diverse T cell-dependent models of autoimmune disease through its receptor DR3. TL1A polymorphisms also confer susceptibility to inflammatory bowel disease. Here, we find that allergic pathology driven by constitutive TL1A expression depends on interleukin-13 (IL-13), but not on T, NKT, mast cells, or commensal intestinal flora. Group 2 innate lymphoid cells (ILC2) express surface DR3 and produce IL-13 and other type 2 cytokines in response to TL1A. DR3 is required for ILC2 expansion and function in the setting of T cell-dependent and -independent models of allergic disease. By contrast, DR3-deficient ILC2 can still differentiate, expand, and produce IL-13 when stimulated by IL-25 or IL-33, and mediate expulsion of intestinal helminths. These data identify costimulation of ILC2 as a novel function of TL1A important for allergic lung disease, and suggest that TL1A may be a therapeutic target in these settings.
Subject(s)
Hypersensitivity/immunology , Hypersensitivity/metabolism , Immunity, Innate , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Animals , Cytokines/metabolism , Disease Models, Animal , Interleukin-13/metabolism , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Intestinal Mucosa/microbiology , Intestinal Mucosa/pathology , Lung/immunology , Lung/metabolism , Lung/pathology , Mast Cells/immunology , Mast Cells/metabolism , Mice , Mice, Knockout , Protein Binding , Receptors, Tumor Necrosis Factor, Member 25/metabolism , Tumor Necrosis Factor Ligand Superfamily Member 15ABSTRACT
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.
Subject(s)
Enteritis/immunology , Interleukin-13/immunology , Tumor Necrosis Factor Ligand Superfamily Member 15/immunology , Animals , CD2 Antigens/genetics , CD2 Antigens/immunology , Colitis/immunology , Colitis/pathology , Dendritic Cells/immunology , Dose-Response Relationship, Immunologic , Enteritis/pathology , Forkhead Transcription Factors/metabolism , Gene Expression Regulation/immunology , Gene Order , HEK293 Cells , Humans , Immunologic Memory/immunology , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/pathology , Interleukin-13/genetics , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Promoter Regions, Genetic , Receptors, Tumor Necrosis Factor, Member 25/metabolism , T-LymphocytesABSTRACT
We earlier proposed that a human endogenous retroviral (HERV) superantigen (SAg) IDDMK(1,2)22 may cause type I diabetes by activating autoreactive T cells. Viral infections and induction of interferon-alpha (IFN-alpha) are tightly associated with the onset of autoimmunity. Here we establish a link between viral infections and IFN-alpha-regulated SAg expression of the polymorphic and defective HERV-K18 provirus. HERV-K18 has three alleles, IDDMK(1,2)22 and two full-length envelope genes, that all encode SAgs. Expression of HERV-K18 SAgs is inducible by IFN-alpha and this is sufficient to stimulate V beta 7 T cells to levels comparable to transfectants constitutively expressing HERV-K18 SAgs. Endogenous SAgs induced via IFN-alpha by viral infections is a novel mechanism through which environmental factors may cause disease in genetically susceptible individuals.
