Cellular and Molecular Regulation of CD8+ T cell memory

CD8 T 细胞记忆的细胞和分子调控

• 批准号: 8660287
• 负责人: Stephen Philip Schoenberger
• 金额: $ 44.25万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660287
• 关键词: Affinity; Antigens; Area; Autoimmunity; Bacteria; Biological Models; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Communication; Cell Death; Cells; Clinical; Data; Development; Disease; Distal; Elements; Event; Exposure to; Foundations; Gene Expression; Generations; Goals; Health; Helper-Inducer T-Lymphocyte; Immune; Immunity; Immunologist; Infection; Inflammation; Inflammatory; Interleukin-2; Laboratories; Laboratory Research; Life; Link; Maintenance; Mediating; Memory; Modeling; Molecular; Molecular Analysis; Monitor; Pathway interactions; Patients; Prevention; Process; Production; Program Development; Publications; Regulation; Reporting; Research; Research Project Grants; Resolution; Role; Series; Shapes; Signal Transduction; Signal Transduction Pathway; Source; Stimulus; System; T cell response; T memory cell; T-Lymphocyte; TNFRSF5 gene; TNFSF10 gene; TNFSF5 gene; Tissue Grafts; Tumor Tissue; Viral; Virus; Work; autocrine; base; cell type; defined contribution; immunogenic; in vivo; in vivo Model; insight; novel; novel strategies; paracrine; pathogen; public health relevance; response; transmission process; tumor eradication

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.

描述（由申请人提供）：CD8+记忆T细胞（CTL）可以赋予对多种病毒和细菌病原体的终身保护，并可以介导肿瘤的根除。相反，如果不适当调节，CTL会引起致病性自身免疫和组织移植物的不良排斥反应。对记忆CTL如何建立和维持的机制理解将允许根据患者临床需要诱导抗原特异性激活与耐受性的新方法。CD4+ T淋巴细胞（TH）向CTL提供“帮助”代表了这一途径中的一个重要控制点，因为它涉及对其功能激活和发育为记忆细胞至关重要的信号传递。我们正在进行的研究已经在这一途径中获得了关键的见解，通过显示TH在CTL启动的早期起作用，建立了一个发展程序，使它们能够进行二次扩增，避免trail介导的激活诱导的细胞死亡（AICD）在再次遇到抗原时。最近，我们已经证明转录调节因子Nab2控制“帮助”与“无助”CTL中TRAIL的诱导。此外，我们已经能够证明一种全新的T对CTL的帮助模型，该模型通过显示cd40介导的APC被TH激活赋予CTL产生自身自分泌IL-2的能力，从而调和了之前两种模型中隐含的差异。综上所述，这些观察结果为CTL记忆产生机制的新探索奠定了基础，并为它们的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传递到CTL的细胞和分子机制的理解。这方面的悬而未决的问题包括：1)识别由th激活的APC提供给CTL的信号，这些信号构成了导致记忆功能的“帮助”信息；2)理解自分泌与旁分泌（即cd4产生）IL-2参与CTL反应的条件；3)对某些免疫原如何产生不依赖th的记忆CTL的机制理解。我们将通过体内感染和免疫模型对原代CTL的功能、表型和分子分析来检查这些区域。我们在这些研究中的中心假设是，TH激活的APC通过CD70-CD27途径传递特异性和可诱导的信号来产生记忆CTL，旁分泌（TH产生的）IL-2对于免疫原性差的抗原的应答很重要，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，导致传递与TH通过cd40激活实现的相同的远端信号。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，并为其在健康和疾病方面的操纵提供更大的潜力。