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在保留宿主组织的同时消除特定病原体的极其有效的手段。然而，这种效率取决于平衡；不受限制的免疫可能会导致自身免疫性疾病，而反应迟缓可能会导致慢性感染和癌症。调节性T细胞(Tregs)通过抑制对自身的免疫反应，维持免疫平衡，在维持这种平衡中起着关键作用。Treg利用许多不同的机制来调节免疫反应的抑制。白介素35(IL-35)是IL-12家族中的一种细胞因子，是一种重要的可溶性抑制因子。IL-35是由IL-12亚单位p35和Epstein-Barr病毒诱导基因3(EBI3)两条蛋白链组成的异源二聚体。IL-35在体内外对免疫细胞的增殖都有很强的抑制作用。Tregs表达编码IL-35的基因 在体质上，而效应器T细胞不是。然而，当幼稚的CD4T细胞在存在IL-35的情况下受到刺激时，他们开始自己分泌IL-35。有趣的是，编码p35和Ebi3的基因通常并不在T细胞中表达；相反，它们被抗原提呈细胞用来制造刺激免疫反应的细胞因子。因此，这些基因在T细胞中的调控仍然不清楚。这项研究建议的实验将推动我们理解IL-35是如何在T细胞中调节的，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。在开发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细胞在为免疫系统提供平衡方面发挥着关键作用。这些细胞对预防自身免疫性疾病至关重要，也抑制了对癌症的免疫力。我们的研究试图确定调节性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.