Elucidating the regulation of interleukin-35, a regulatory cytokine, in T cells

描述（由申请人提供）：适应性免疫系统是一种非常有效的消除特定病原体同时保留宿主组织的方法。然而，这种效率取决于平衡;不受限制的免疫可能导致自身免疫性疾病，而缓慢的反应可能导致慢性感染和癌症。调节性T细胞（Regulatory T cells，Tcells）通过抑制对自身的免疫反应和维持免疫稳态，在维持这种平衡中发挥着关键作用。它利用许多不同的机制来介导免疫应答的抑制。白细胞介素-35（IL-35）是IL-12家族的一种细胞因子，已成为一种重要的可溶性抑制介质。IL-35作为两条蛋白链的异源二聚体分泌，IL-12亚基p35和EB病毒诱导基因3（Ebi 3）。IL-35是体外和体内免疫细胞增殖的有效抑制剂。胸腺细胞表达编码IL-35的基因 组成型，而效应T细胞没有。然而，当幼稚CD 4 T细胞在IL-35存在下被刺激时，它们开始自身分泌IL-35。有趣的是，编码p35和Ebi 3的基因通常不在T细胞中表达;相反，它们被抗原呈递细胞用来产生刺激免疫应答的细胞因子。因此，这些基因在T细胞中的调控仍不清楚。这项研究建议的实验将推动我们理解IL-35如何在T细胞中调节，并阐明IL-35介导抑制T细胞增殖和转化为IL-35产生细胞的分子机制。了解这些机制对于开发针对自身免疫和癌症的新策略至关重要。

DESCRIPTION (provided by applicant): The adaptive immune system is an extremely efficient means of eliminating specific pathogens while sparing host tissues. However, this efficiency is dependent on balance; unrestrained immunity can lead to autoimmune disease while a sluggish response can lead to chronic infections and cancer. Regulatory T cells (Tregs) play a critical role in maintaining this balance by suppressing the immune response to self and maintaining immune homeostasis. Tregs utilize many distinct mechanisms to mediate suppression of the immune response. Interleukin-35 (IL-35), a cytokine from the IL-12 family, has emerged as an important soluble mediator of suppression. IL-35 is secreted as a heterodimer of two protein chains, the IL-12 subunit p35 and Epstein-Barr Virus induced gene 3 (Ebi3). IL-35 is a potent inhibitor of immune cell proliferation in vitro and in vivo. Tregs express the genes encoding IL-35 constituitively, while effector T cells do not. However, when naive CD4 T cells are stimulated in the presence of IL-35, they begin to secrete it themselves. Interestingly, the genes encoding p35 and Ebi3 are not generally expressed in T cells; rather, they are utilized by antigen-presenting cells to make cytokines that stimulate the immune response. As such, the regulation of these genes in T cells is still unclear. This research proposal suggests experiments that will propel our understanding of how IL-35 can be regulated in T cells, and elucidate the molecular mechanisms used by IL-35 to mediate suppression of T cell proliferation and conversion to IL-35 producing cells. Understanding these mechanisms is of crucial importance when developing new strategies targeting autoimmunity and cancer.