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.
Meylan
F
F
Immunoregulation Section, Autoimmunity Branch, NIAMS, Bethesda, Maryland, USA.
Song
Y-J
YJ
Fuss
I
I
Villarreal
S
S
Kahle
E
E
Malm
I-J
IJ
Acharya
K
K
Ramos
H L
HL
Lo
L
L
Mentink-Kane
M M
MM
Wynn
T A
TA
Migone
T-S
TS
Strober
W
W
Siegel
R M
RM
D000818:Animals; D018801:CD2 Antigens / Q000235:genetics / Q000276:immunology; D003092:Colitis / Q000276:immunology / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D004751:Enteritis / Q000276:immunology* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D023061:Gene Order; D057809:HEK293 Cells; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000473:pathology; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000378:metabolism; D013601:T-Lymphocytes; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000276:immunology*
D018801:CD2 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018793:Interleukin-13; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506034:Tnfrsf25 protein, mouse; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15