Regulation of memory CD8 T cell development

描述(申请人提供)：记忆CD8 T细胞在调节对传染病的长期免疫中发挥关键作用。开发长寿记忆CD8 T细胞是目前许多疫苗的首要目标，这些疫苗将对抗艾滋病毒、疟疾和丙型肝炎等慢性感染，也将对抗某些类型的癌症。记忆性CD8T细胞提供了长寿的免疫保护，因为它们在抗原相遇时比普通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CD8 T细胞可以持续很长时间(长达人的一生)，并被赋予许多类似干细胞的特性，如端粒酶表达和通过体内平衡转换进行自我更新的能力。这些功能属性，以及病原体特异性T细胞前体频率的纯粹增加，构成了长期记忆T细胞介导的免疫的基础。了解防止二次感染的长寿记忆T细胞是如何形成和维持的，这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。我们已经发现了一条控制成熟的抗病毒记忆CD8T细胞及其前体细胞形成的新途径，涉及IL-10、IL-21和STAT3的作用。基于我们的发现，我们假设记忆细胞的命运并不一定是在激活的CD8 T细胞中编程的，而是需要来自IL-10和IL-21的信号来维持成熟的记忆CD8 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的CD8 T细胞容易自发地分化为效应细胞，IL-10/IL-21/SOCS3起到缓冲记忆CD8 T细胞免受稳态或旁观者炎症爆发的作用，以维持记忆细胞的潜力和保护性反应。在这项资助中，我们将使用最先进的技术来确定(1)在感染过程中，IL-10/IL-21/STAT3信号何时影响记忆细胞的命运，(2)T细胞是否是记忆CD8 T细胞发育的生理相关生产者或IL-10和IL-21，(3)在没有STAT3的情况下，阻断IL-2或IL-12信号是否拯救记忆CD8 T细胞的发育，以及(4)STAT3和STAT4/STAT5如何相互控制‘效应器’和‘记忆’CD8 T细胞的基因表达。这项工作具有很高的影响力，因为它为调节记忆CD8 T细胞分化和动态平衡的细胞因子和转录因子提供了新的机械性见解，这可能导致在疫苗接种、癌症治疗和其他类型的基于免疫的治疗中改进对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.