Regulation of effector T cells that mediate inflammatory responses

OX40是提供T细胞共刺激信号的肿瘤坏死因子受体超家族成员。在T细胞介导的免疫疾病中，如自身免疫、变态反应性疾病和感染性疾病以及移植物抗宿主病(GVHD)，炎症部位存在OX40淋巴细胞和OX40配体(OX40L)细胞。这些观察表明，OX40-OX40L相互作用在T细胞介导的炎症反应中起重要作用。因此，我们试图阐明OX40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OX40介导的T细胞炎症机制。关于第一个机制，我们已经证明OX40信号优先促进效应记忆CD4T细胞的产生，而不是中枢记忆CD4T细胞的产生，效应记忆CD4T细胞主要参与包含炎症的器官特异性免疫反应。这可以解释之前的几个发现，即OX40增强了器官特异性炎症，但不能增强全身免疫反应。其次，我们已经证明，刻意的OX40信号抑制了可诱导调节性T细胞(ITreg)的体外分化，在转化生长因子β存在的情况下，这种细胞可以由初始的CD4T细胞在抗原刺激下被诱导。相反，在Treg可诱导刺激过程中抑制OX40信号可促进iTreg细胞的生成。这些结果表明，过多的OX40信号可能导致Treg介导的免疫耐受诱导失败，而抑制OX40信号可能会增强Treg介导的免疫耐受。为了充分了解OX40在T细胞介导的炎症中的作用，还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.