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，产生B细胞反应和调节体内平衡。在某些情况下，活化的T细胞也对宿主有害，介导自身免疫性疾病、过敏反应、免疫病理和移植组织的排斥反应。幼稚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，目前仍未完全了解。T细胞激活的早期阶段对T细胞分化途径的编程至关重要，这一过程对炎症水平极其敏感。我们已经证明，初始表型T细胞在TCR接合后5小时内迅速产生TNF。这一结果是出乎意料的，因为人们认为初始T细胞只有在经历分化过程后才能获得效应功能，这表明初始T细胞在免疫反应的先天阶段产生这种炎症细胞因子。我们最近的数据表明，T细胞产生的TNF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TNF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，这种功能是由TNF的产生介导的。该研究计划的长期目标是进一步表征T细胞产生的TNF在T细胞反应产生中的作用，并确定在感染后早期拮抗TNF活性是否会增强免疫反应。需要验证的具体假设是，T细胞产生的TNF对功能性细胞免疫的发展具有重要的调节功能。我们建议通过以下具体目标来评估T细胞产生的TNF的重要性：具体目标#1：确定T细胞产生的TNF调节病毒特异性T细胞反应产生的机制。特异性目的2：确定在感染和疫苗接种后，tnf信号的短暂阻断是否会增强病毒特异性T细胞反应的产生。公共卫生相关性：拟议的研究计划将促进我们对免疫系统如何对感染性病原体作出反应的基本理解。这些研究的结果可能导致开发更有效的疫苗，产生更强的抗病毒免疫。

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.