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

描述（由申请人提供）：适应性免疫系统是消除特定病原体同时保护宿主组织的极其有效的手段。然而，这种效率取决于平衡；不受限制的免疫力可能导致自身免疫性疾病，而反应迟缓可能导致慢性感染和癌症。调节性 T 细胞 (Treg) 通过抑制对自身的免疫反应并维持免疫稳态，在维持这种平衡方面发挥着关键作用。 Tregs 利用许多不同的机制来介导免疫反应的抑制。白介素 35 (IL-35) 是 IL-12 家族的一种细胞因子，已成为重要的可溶性抑制介质。 IL-35 作为两条蛋白链的异二聚体分泌，即 IL-12 亚基 p35 和 Epstein-Barr 病毒诱导基因 3 (Ebi3)。 IL-35 是体外和体内免疫细胞增殖的有效抑制剂。 Tregs 表达编码 IL-35 的基因 组成型细胞，而效应 T 细胞则不然。然而，当幼稚 CD4 T 细胞在 IL-35 存在的情况下受到刺激时，它们会开始自行分泌 IL-35。有趣的是，编码 p35 和 Ebi3 的基因通常不在 T 细胞中表达；相反，它们被抗原呈递细胞利用来产生刺激免疫反应的细胞因子。因此，这些基因在 T 细胞中的调控仍不清楚。这项研究计划提出的实验将推动我们了解 IL-35 如何在 T 细胞中受到调节，并阐明 IL-35 用于介导抑制 T 细胞增殖和转化为 IL-35 产生细胞的分子机制。在制定针对自身免疫和癌症的新策略时，了解这些机制至关重要。 公共卫生相关性：调节性 T 细胞在维持免疫系统平衡方面发挥着关键作用。这些细胞对于预防自身免疫性疾病至关重要，并且还能抑制对癌症的免疫力。我们的研究旨在确定调节性 T 细胞如何调节免疫；阐明这些途径对于开发更好的自身免疫和癌症治疗方法至关重要。

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. PUBLIC HEALTH RELEVANCE: Regulatory T cells play a critical role in providing balance to the immune system. These cells are critical for protection against autoimmune diseases, and also inhibit immunity to cancers. Our research seeks to determine how regulatory T cells modulate immunity; elucidating these pathways is critical to developing better treatments for both autoimmunity and cancer.