OX40 is required for regulatory T cell-mediated control of colitis.
The immune response in the gastrointestinal tract is a tightly controlled balance between effector and regulatory cell responses. Here, we have investigated the role of OX40 in influencing the balance between conventional T cells and Foxp3+ regulatory T (T reg) cells. Under steady-state conditions, OX40 was required by T reg cells for their accumulation in the colon, but not peripheral lymphoid organs. Strikingly, under inflammatory conditions OX40 played an essential role in T reg cell-mediated suppression of colitis. OX40(-/-) T reg cells showed reduced accumulation in the colon and peripheral lymphoid organs, resulting in their inability to keep pace with the effector response. In the absence of OX40 signaling, T reg cells underwent enhanced activation-induced cell death, indicating that OX40 delivers an important survival signal to T reg cells after activation. As OX40 also promoted the colitogenic Th1 response, its expression on T reg cells may be required for effective competition with OX40-dependent effector responses. These results newly identify a key role for OX40 in the homeostasis of intestinal Foxp3+ T reg cells and in suppression of colitis. These fi ndings should be taken into account when considering OX40 blockade for treatment of IBD.
Griseri
Thibault
T
Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, England, UK.
Asquith
Mark
M
Thompson
Claire
C
Powrie
Fiona
F
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D002452:Cell Count; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D003092:Colitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics; D016023:Integrins / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000235:genetics; D008213:Lymphocyte Activation / Q000276:immunology; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053278:OX40 Ligand; D053262:Receptors, OX40 / Q000235:genetics / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D048069:Tumor Necrosis Factors / Q000235:genetics
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018398:Homeodomain Proteins; D016023:Integrins; D020381:Interleukin-17; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors; C071777:integrin alpha4beta7; C064658:RAG-1 protein; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse