Regulation of Virus-Specific T cell Responses by TNF

描述(由申请人提供)：T细胞参与免疫系统的许多有益方面，包括控制感染，肿瘤监测，B细胞反应的产生，以及体内平衡的调节。在某些情况下，激活的T细胞也对宿主有害，介导自身免疫性疾病、过敏反应、免疫病理学和移植组织的排斥反应。初始T细胞的激活是一个严格控制的过程，涉及一个复杂的信号事件网络，至今仍不完全清楚。T细胞活化的早期阶段对T细胞分化途径的编程至关重要，这一过程对炎症程度极其敏感。我们已经证明，幼稚的表型T细胞在TCR参与的5小时内迅速产生肿瘤坏死因子。这一结果是出乎意料的，因为原始T细胞被认为只有在经历分化过程后才能获得效应器功能，这表明原始T细胞在免疫反应的固有阶段产生这种炎性细胞因子。我们最近的数据表明，T细胞产生的肿瘤坏死因子对抗病毒反应的产生具有抑制作用，因为与野生型T细胞相比，感染后缺乏肿瘤坏死因子的病毒特异性T细胞的出现频率明显更高。这些发现揭示了抗原特异性T细胞的一种新的自我调节功能，这种功能是通过产生肿瘤坏死因子来介导的。这项拟议研究计划的长期目标是进一步确定T细胞产生的肿瘤坏死因子在产生T细胞反应中的作用，并确定在感染后早期拮抗肿瘤坏死因子活性是否会增强免疫反应。需要检验的具体假设是，T细胞产生的肿瘤坏死因子对功能性细胞免疫的发展具有重要的调节功能。我们建议通过以下特定目的来评估T细胞产生的肿瘤坏死因子的重要性：特异性目的1：确定T细胞产生的肿瘤坏死因子调节病毒特异性T细胞反应产生的机制。具体目的2：确定短暂阻断肿瘤坏死因子信号是否会增强感染和接种后病毒特异性T细胞反应的产生。公共卫生相关性：拟议的研究倡议将促进我们对免疫系统如何应对传染病病原体的基本理解。这些研究的结果可能会导致开发出更有效的疫苗，产生更强的抗病毒免疫力。

DESCRIPTION (provided by applicant): T cells are involved in many beneficial aspects of the immune system including the control of infections, tumor surveillance, generation of B cell responses, and regulation of homeostasis. In some instances, activated T cells are also detrimental to a host, mediating autoimmune disease, allergic reactions, immunopathology, and the rejection of transplanted tissues. The activation of naive T cells is a tightly controlled process, involving a complex network of signaling events that is still not completely understood. The early stages of T cell activation are critical to the programming of differentiation pathways for T cells, and this process is extremely sensitive to levels of inflammation. We have shown that naive phenotype T cells rapidly produce TNF within 5 hours of TCR engagement. This result was unexpected because naive T cells are thought to acquire effector functions only after undergoing a differentiation process and suggests that naive T cells produce this inflammatory cytokine during the innate phase of the immune response. Our recent data indicate that T cell-produced TNF has a suppressive effect on the generation of anti-viral responses, as TNF-deficient virus-specific T cells are present at significantly higher frequencies after infection as compared to wild type T cells. These findings reveal a novel self-regulatory function for antigen-specific T cells that is mediated by the production of TNF. The long-term goals for this proposed research plan are to further characterize the role of T cell-produced TNF in the generation of T cell responses and to determine if antagonizing TNF-activity at early times after infection will enhance immune responses. The specific hypothesis to be tested is that T cell- produced TNF has important regulatory functions for the development of functional cellular immunity. We propose to evaluate the importance of T cell-produced TNF by the following specific aims: SPECIFIC AIM#1: To determine the mechanisms by which T cell-produced TNF regulates the generation of virus-specific T cell responses. SPECIFIC AIM#2: To determine if a transient blockade of TNF-signaling will enhance the generation of virus-specific T cell responses after infection and vaccination. PUBLIC HEALTH RELEVANCE: The proposed research initiative will advance our basic understanding of how the immune system responds to infectious pathogens. The results of these studies may lead to the development of more effective vaccines that generate stronger anti-viral immunity.