TRAIL-mediated regulation of T help for CTL

描述（由申请人提供）：细胞免疫学中一个长期存在的悖论涉及CD4+“辅助”T细胞（TH）在体内引发细胞毒性CD8+ T淋巴细胞（CTL）反应的条件要求。虽然通过交叉引物介导的CTL依赖于CD4+ T细胞的存在，但许多其他细胞，包括针对许多病毒和细菌的细胞，显然可以在CD4+ T细胞缺席的情况下进行。我们最近证明，在这两种情况下，TH赋予CTL免疫记忆的关键特征；再次暴露于抗原后2度扩张的能力。这一发现为以前对th依赖性和th非依赖性CTL反应的矛盾观察提供了统一的解释，并为理解CD8 T细胞如何受CD4+ T细胞调节提供了新的理论框架。本研究的目的是确定T帮助被赋予CTL的机制，并确定“帮助”如何影响CD8 T细胞的功能发育。我们的假设是，TH通过离散的感应信号传递给CD8+ T细胞，这些信号修改了指导CTL发育的指导程序，使其包括2度扩张的能力。因此，我们的具体目标是：1)确定在启动期间由TH“编程”的CTL发育和功能的那些方面；2)定义赋予“受助”CTL 2度扩展能力的信号；3)定义导致“受助”CTL与“无助”CTL在2度刺激下不同命运的分子途径。我们的初步数据表明，后一过程的一个主要组成部分涉及通过肿瘤坏死因子（TNF）相关凋亡诱导配体(TRAIL)/TRAIL- r2 （DR5）途径介导的激活诱导凋亡。我们的实验将涉及内源性和转基因/敲除CD8+ T细胞在细胞和分子水平上对各种体内抗原挑战的1度和2度反应的研究。我们预计该项目将使我们清楚地了解T帮助CTL的机制，并将确定如何策略性地操纵这一过程，以促进对感染性病原体的有益反应，以及抑制病理性自身免疫。

DESCRIPTION (provided by applicant): A long-standing paradox in cellular immunology concerns the conditional requirement for CD4+ 'helper' Tcells (TH) in priming of cytotoxic CD8+ T lymphocytes (CTL) responses in vivo. Whereas CTL mediated via cross-priming depend on the presence of CD4+ T cells, many others, including those against many viruses and bacteria, can apparently proceed in their absence. We have recently demonstrated that in both settings, TH endows CTL with a key characteristic of immune memory; the capacity for 2 degree expansion upon re-exposure to antigen. This finding offers a unifying explanation for previous paradoxical observations of TH-dependent and TH-independent CTL responses and provides a new theoretical framework for understanding how CD8 T cells are regulated by CD4+ T cells. The goal of this research is to define the mechanism through which T help is conferred to CTL and to determine how 'help' influences the functional development of CD8 T cells. Our hypothesis is that TH is transmitted to CD8+ T cells through discrete inductive signals that modify the instructional program guiding CTL development to include the capacity for 2 degree expansion. Our specific goals are therefore I) to identify those aspects of CTL development and function which are "programmed" by TH during priming, II) to define the signals through which the capacity for 2 degree expansion is conferred to "helped" CTL, and III) to define the molecular pathways that lead to the disparate fates of 'helped' versus 'helpless' CTL upon 2 degree stimulation. Our preliminary data indicate that a major component of this latter process involves activation-induced apoptosis mediated via tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)/TRAIL-R2 (DR5) pathway. Our experiments will involve study of the 1 degree and 2 degree responses of endogenous and transgenic/knockout CD8+ T cells at the cellular and molecular level following a variety of in vivo antigenic challenges. We anticipate that this project will allow a clear understanding of the mechanism of T help for CTL and will identify how this process can be strategically manipulated to promote beneficial responses against infectious pathogens as well as inhibiting pathologic autoimmunity.