Cellular and Molecular Regulation of CD8+ T cell memory

描述(申请人提供)：CD8+记忆T细胞(CTL)可以提供终生保护，免受各种病毒和细菌病原体的影响，并可以介导肿瘤的根除。相反，如果调控不当，CTL会导致病理性自身免疫和组织移植物的不良排斥反应。从机制上理解记忆CTL是如何建立和维持的，将允许根据患者的临床需要，采用新的方法来诱导抗原特异性激活与耐受。由CD4+T淋巴细胞(TH)向CTL提供“帮助”是这一途径中的一个重要控制点，因为它涉及到信号的传递，这些信号对于它们的功能激活和发育为记忆细胞至关重要。我们正在进行的研究已经在这一途径中产生了关键的见解，表明TH在CTL启动的早期就起作用，以建立一个发育程序，使它们能够经历二次扩张，并避免TRAIL介导的激活诱导的细胞死亡(AICD)。最近，我们发现转录调控因子Nab2控制着“有帮助”与“无助”的CTL中TRAIL的诱导。此外，我们已经能够证明一个全新的CTL T Help模型，该模型通过证明CD40介导的TH激活APC赋予CTL产生自己的自分泌IL-2的能力，从而协调了先前两个模型中隐含的差异。综上所述，这些观察结果为新的探索CTL记忆产生的机制奠定了基础，并为其策略性操纵提供了新的可能性。本研究的目的是为了进一步了解TH向CTL传递的细胞和分子机制。这方面的悬而未决的问题包括：1)识别TH激活的APC向CTL提供的信号，这些信号构成导致记忆功能的“帮助”消息；2)了解自分泌与旁分泌(即由CD4产生的)IL-2参与CTL反应的条件；以及3)从机制上理解某些免疫原如何产生TH非依赖性的记忆性CTL。我们将使用体内感染和免疫模型，通过初级CTL的功能、表型和分子分析来检查这些区域中的每一个。我们在这些研究中的中心假设是，TH激活的APC通过CD70-CD27途径传递特异和可诱导的信号来产生记忆性CTL，旁分泌(TH产生的)IL-2对于免疫原性差的抗原的反应可能是重要的，TH非依赖性CTL是通过炎症刺激直接和间接激活APC而产生的，导致与TH通过CD40激活实现的相同的远端信号的传递。该项目的成功完成将为记忆CTL的产生奠定坚实的实验和理论基础，并使其在健康和疾病中的操作具有更大的潜力。

DESCRIPTION (provided by applicant): CD8+ memory T cells (CTL) can confer lifelong protection from a wide variety of viral and bacterial pathogens, and can mediate the eradication of tumors. Conversely, CTL cause pathogenic autoimmunity and undesirable rejection of tissue grafts when not properly regulated. A mechanistic understanding of how memory CTL are established and maintained would allow for new approaches to inducing antigen-specific activation versus tolerance according to a patient's clinical need. The provision of "help" by CD4+ T lymphocytes (TH) to CTL represents an important control point in this pathway as it involves the transmission of signals that are critical for their functional activation and development into memory cells. Our ongoing studies have yielded key insights in this pathway by showing TH acts early during CTL priming to establish a program of development which allows them to undergo secondary expansion and avoid of TRAIL-mediated activation-induced cell death (AICD) upon reencounter with antigen. More recently, we have shown that the transcriptional regulator Nab2 controls the induction of TRAIL in "helped" versus "helpless" CTL. Furthermore, we have been able to prove an entirely new model of T help for CTL that reconciles differences implicit in the two previous models by showing that CD40-mediated APC activation by TH endows CTL with the capacity to produce their own autocrine IL-2. Taken together, the observations lay the foundation for a new exploration of the mechanisms underlying the generation of CTL memory and offer new possibilities for their strategic manipulation. The goal of this research is to complete our understanding of the cellular and molecular mechanism through which TH is transmitted to CTL. Outstanding questions in this regard include 1) identification of the signals provided by TH-activated APC to CTL that constitute the "help" message leading to memory functionality, 2) understanding the conditions under which autocrine versus paracrine (i.e. CD4-produced) IL-2 is involved in CTL responses, and 3) achieving a mechanistic understanding of how certain immunogens generate TH-independent memory CTL. We will examine each of these areas through the functional, phenotypic, and molecular analysis of primary CTL using in vivo models of infection and immunity. Our central hypothesis in these studies is that TH-activated APC transmit specific and inducible signals via the CD70-CD27 pathway to generate memory CTL, that paracrine (TH-produced) IL-2 can be important for responses against poorly immunogenic antigens, and that TH-independent CTL are produced by direct and indirect activation of APC by inflammatory stimuli, leading to transmission of the same distal signals as those achieved by TH through CD40-activation. Successful completion of this project will place the generation of memory CTL on a firm experimental and theoretical foundation and allow a greater potential for it's manipulation in health and disease.