Regulation of effector T cells that mediate inflammatory responses

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OX40 is a member of TNF receptor superfamily molecules that provide T-cell costimulatory signals. The presence of (OX40^+ lymphocytes and OX40 ligand^+ (OX40L)^+ cells at the sites of inflammation in T cell-mediated immune disorders, such as autoimmunity, allergic and infectious diseases, and GVHD is well documented. These observations suggest important roles for OX40-OX40L interactions in T-cell mediated inflammatory responses. We thus have attempted to elucidate the critical roles for OX40 on the inflammatory responses. In this study, we have founded at least two distinct mechanisms for OX40-mediated T cell inflammation. Concerning the first mechanism, we have demonstrated that OX40 signals preferentially promote the generation of effector memory CD4 T cells, which are mainly involved in organ-specific immune responses containing inflammation, rather than central memory CD4 T cells, which mediate systemic immune responses. This can explain several previous findings that OX40 enhances organ-specific inflammation, but not systemic immune responses. Secondly, we have shown that deliberate OX40 signals suppress in vitro differentiation of inducible regulatory T (iTreg) cells, which can be induced from naive CD4 T cells upon stimulation with antigen in the presence of TGFβ. In contrast, inhibition of OX40 signals during the Treg inducible stimulation promoted iTreg cell generation. These results suggest that excessive OX40 signals may lead to a failed induction of Treg-mediated immune tolerance, and that suppression of OX40 signals may enhance Treg-mediated immune tolerance. To fully understand the OX40 roles on T-cell mediated inflammation, further in vivo studies are required.