Cellular and Molecular Regulation of CD8+ T cell memory

描述（由申请人提供）：CD 8+记忆T细胞（CTL）可以提供终身保护，免受各种病毒和细菌病原体的侵害，并可以介导肿瘤的根除。相反，当不适当调节时，CTL引起致病性自身免疫和组织移植物的不期望的排斥。对记忆性CTL如何建立和维持的机制性理解将允许根据患者的临床需要诱导抗原特异性激活与耐受的新方法。由CD 4 + T淋巴细胞（TH）向CTL提供“帮助”代表了该途径中的重要控制点，因为它涉及对其功能激活和发育成记忆细胞至关重要的信号的传递。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，通过显示TH在CTL引发过程中的早期作用，以建立一个发展计划，该计划允许它们进行二次扩增，并避免再次遇到抗原时TRAIL介导的活化诱导的细胞死亡（AICD）。最近，我们已经表明，转录调节因子Nab 2控制诱导的TRAIL在“帮助”与“无助”的CTL。此外，我们已经能够证明一个全新的模型的T细胞帮助CTL，调和在两个先前的模型中隐含的差异，显示CD 40介导的APC激活TH赋予CTL的能力，产生自己的自分泌IL-2。综上所述，这些观察结果为新探索CTL记忆产生的机制奠定了基础，并为其策略操纵提供了新的可能性。本研究的目的是完成我们对TH传递给CTL的细胞和分子机制的理解。这方面的突出问题包括1）鉴定TH激活的APC向CTL提供的信号，其构成导致记忆功能的“帮助”信息，2）理解自分泌与旁分泌（即CD 4产生的）IL-2参与CTL应答的条件，和3）实现某些免疫原如何产生TH非依赖性记忆CTL的机制理解。我们将通过使用感染和免疫的体内模型对初级CTL进行功能、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CD 70-CD 27通路传递特异性和诱导性信号，产生记忆CTL，（TH-产生的）IL-2对于针对免疫原性差的抗原的应答可能是重要的，并且TH-非依赖性CTL是通过炎症刺激直接和间接激活APC产生的，导致与TH通过CD 40活化实现的那些相同的远端信号的传输。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，并为健康和疾病的操纵提供更大的潜力。

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.