Regulation of effector T cells that mediate inflammatory responses

OX 40是提供T细胞共刺激信号的TNF受体超家族分子的成员。在T细胞介导的免疫疾病（如自身免疫、过敏性和感染性疾病以及GVHD）的炎症部位存在OX 40 ^+淋巴细胞和OX 40配体^+（OX 40 L）^+细胞已得到充分证实。这些观察结果表明OX 40-OX 40 L相互作用在T细胞介导的炎症反应中的重要作用。因此，我们试图阐明OX 40在炎症反应中的关键作用。在这项研究中，我们发现了至少两种不同的机制OX 40介导的T细胞炎症。关于第一种机制，我们已经证明，OX 40信号优先促进效应记忆CD 4 T细胞的产生，其主要参与包含炎症的器官特异性免疫应答，而不是介导全身免疫应答的中央记忆CD 4 T细胞。这可以解释先前的几项发现，即OX 40增强器官特异性炎症，但不增强全身免疫反应。其次，我们已经表明，故意的0X 40信号抑制诱导型调节性T（iTreg）细胞的体外分化，所述诱导型调节性T（iTreg）细胞可以在TGFβ存在下在用抗原刺激后从初始CD 4 T细胞诱导。相反，在Treg诱导型刺激期间抑制0X 40信号促进iTreg细胞生成。这些结果表明，过量的OX 40信号可能导致Treg介导的免疫耐受的诱导失败，并且抑制OX 40信号可能增强Treg介导的免疫耐受。为了充分了解OX 40在T细胞介导的炎症中的作用，需要进一步的体内研究。

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.