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.
The Journal of experimental medicine
699 - 709
Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, England, UK.
Intestinal Mucosa, Colon, Lymphoid Tissue, T-Lymphocyte Subsets, CD4-Positive T-Lymphocytes, Animals, Mice, Inbred C57BL, Mice, Transgenic, Mice, Knockout, Mice, Colitis, Disease Models, Animal, Antigens, CD45, Tumor Necrosis Factors, Homeodomain Proteins, Membrane Glycoproteins, Integrins, Interleukin-17, Cell Count, Lymphocyte Activation, Apoptosis, Cell Proliferation, Cell Movement, Gene Expression, T-Lymphocytes, Regulatory, Forkhead Transcription Factors, Receptors, OX40, Interferon-gamma