Regulation of memory CD8 T cell development

描述（由申请人提供）：记忆性CD 8 T细胞在介导针对感染性疾病的长期免疫中发挥关键作用。开发长寿记忆CD 8 T细胞目前是许多疫苗的首要目标，这些疫苗将对抗慢性感染，如艾滋病毒，疟疾和丙型肝炎，以及某些类型的癌症。记忆性CD 8 T细胞提供长期的免疫保护，因为它们在遇到抗原时比原始T细胞更快地增殖、分泌抗病毒细胞因子并杀死感染的细胞。记忆性CD 8 T细胞可以持续很长时间（长达一个人的一生），并且许多干细胞样特性被赋予这些细胞，例如端粒酶表达和通过稳态周转自我更新的能力。这些功能属性，沿着病原体特异性T细胞前体频率的急剧增加，构成了长期记忆T细胞介导的免疫的基础。 了解如何形成和维持长寿命的记忆T细胞，以防止继发性感染是一个重要的研究领域，因为它们在人类健康中发挥着深远的作用。我们已经确定了一种控制成熟抗病毒记忆CD 8 T细胞及其前体形成的新途径，该途径涉及IL-10，IL-21和STAT 3的作用。基于我们的发现，我们假设记忆细胞命运不一定在活化的CD 8 T细胞中被“编程”，而是需要来自IL-10和IL-21的信号传导来维持成熟的记忆CD 8 T细胞分化状态和中央记忆（TCM）特性。在缺乏这些信号的情况下，我们假设抗原特异性CD 8 T细胞倾向于自发效应细胞分化，并且IL-10/IL-21/SOCS 3用于缓冲来自稳态或旁观者炎性爆发的记忆CD 8 T细胞，以维持记忆细胞潜能和保护性应答。在这项授权中，我们将使用现有技术来确定（1）在感染期间IL-10/IL-21/STAT 3信号传导何时影响记忆细胞命运，（2）T细胞是否是记忆CD 8 T细胞发育的生理相关生产者或IL-10和IL-21，（3）在STAT 3不存在的情况下阻断IL-2或IL-12信号传导是否挽救记忆CD 8 T细胞发育，（4）STAT 3和STAT 4/STAT 5共同调控效应和记忆性CD 8 T细胞基因表达。这项工作具有很高的影响力，因为它为调节记忆CD 8 T细胞分化和稳态的细胞因子和转录因子提供了新的机制见解，这可能导致在疫苗接种，癌症治疗和其他类型的免疫治疗期间改善T细胞分化和功能的治疗调节。

DESCRIPTION (provided by applicant): Memory CD8 T cells play a critical role in mediating long-term immunity against infectious disease. Developing long-lived memory CD8 T cells is currently the paramount goal of many vaccines that will fight chronic infections, such as HIV, malaria and Hepatitis C, and also against certain types of cancers. Memory CD8 T cells provide long-lived immunological protection because they proliferate, secrete antiviral cytokines and kill infected cells more rapidly than nave T cells upon antigen encounter. Memory CD8 T cells can persist for great lengths of time (up to one's lifetime) and a number of stem cell-like properties are bestowed onto these cells, such as telomerase expression and the ability to self-renew through homeostatic turnover. These functional attributes, along with the sheer increase in precursor frequency of pathogen-specific T cells, constitute the basis of long-term memory T cell-mediated immunity. Understanding how long-lived memory T cells that protect against secondary infections are formed and maintained is an important area of research because of their profound role in human health. We have identified a novel pathway controlling the formation of mature antiviral memory CD8 T cells and their precursors that involves the actions of IL-10, IL-21 and STAT3. Based on our findings, we hypothesize that memory cell fates are not necessarily "programmed" in activated CD8 T cells, but rather, require signaling from IL-10 and IL-21 to sustain mature memory CD8 T cell differentiation states and central memory (TCM) properties. In the absence of these signals, we postulate that antigen-specific CD8 T cells are prone to spontaneous effector cell differentiation and IL-10/IL-21/SOCS3 act to buffer memory CD8 T cells from steady-state or bystander inflammatory bursts to sustain memory cell potential and protective responses. In this grant we will use state of the art techniques to determine (1) when during infection IL-10/IL-21/STAT3 signaling influences memory cell fates, (2) if T cells are the physiologically relevant producers or IL-10 and IL-21 for memory CD8 T cell development, (3) whether blocking IL-2 or IL-12 signaling rescues memory CD8 T cell development in the absence of STAT3, and (4) how STAT3 and STAT4/STAT5 reciprocally control 'effector' and 'memory' CD8 T cell gene expression. This work is of high impact because it provides new mechanistic insight into cytokines and transcription factors that regulate memory CD8 T cell differentiation and homeostasis, and this could lead to improved therapeutic modulation of T cell differentiation and function during vaccination, cancer treatments and other types of immune-based therapies.