Biology and Function of anti-HSV CD8 T Cells

目前关于建立和维持长期T细胞记忆的概念提出，记忆T细胞是 来源于一小部分存活的效应性T细胞。使用皮肤HSV-1感染模型 C57BL/6小鼠，我们发现控制感染的能力高度依赖于HSV-1-1的存在。 特异性的CD4？和CD8？T细胞，主要由CD8？T细胞表达细胞溶解功能和 能够合成干扰素-γ(干扰素-/)。表达CTL功能的能力与 IL-2受体c-链CD25表达增加。这一观察结果得出的结论是， 高水平的CD25是HSV特异性CTL活性表达的必备条件。然而，CD8的一个亚群？ T细胞，既存在于引流区域淋巴结内，也存在于脾内。 对感染的反应，已经确定。这些细胞在体外经过抗原刺激后合成干扰素-α，而不需要 表达高水平的CD25。在所有其他方面，这些CD8+T细胞都具有激活的所有特征 细胞，这表明它们可能代表了一群只能合成细胞因子而不是 表达穿孔素依赖的CTL功能，或可能是记忆性CD8？T细胞的直接祖细胞。假设是为了 需要指出的是，CD8T细胞亚群代表了一种能够直接进入记忆的细胞谱系 无需通过完整的激活程序即可获得CTL功能。将研究五个具体目标。在……里面 目的1、在体内获得CD8T细胞亚群的细胞溶解和细胞因子合成功能 详细分析了感染的整个初始反应过程。此外，定义的CD8？T细胞将是 转移到受体动物身上，并确定后代的功能。在目标2中，这个亚群的能力 对长期记忆的贡献将通过领养转移到适当的受体小鼠来评估。这个能力将会 直接与从长期康复的小鼠中获得的“真正的”记忆CD8？T细胞进行比较。目标3将 使用新开发的一种方法解决不同CD8？T细胞亚群的激活状态和功能 转基因模型，通过对重要信号介质的分析，以及细胞存活为 通过检测凋亡细胞的百分比和抗凋亡分子的表达来确定。目标4将 确定不同CD8T细胞的表型特征，以了解不同疾病的分子基础 体内的迁移模式。目标5将讨论不同细胞因子种类在克隆扩增和 分化不同的CD8？T细胞，重点放在负责增殖和 差异化。总体而言，该提案将确定CD8+0D25 neg T细胞是否对记忆有贡献，是一种 不同的效应细胞亚群，具有独特的特征，或发育死胡同。更深入地了解 CD8 T细胞生物学将是这些研究的结果。

Current concepts of the establishment and maintenance of long-term T cell memory propose that memory T cells are derived from a small; surviving subpopulation of effector T cells. Using a model of cutaneous HSV-1 infection in C57BL/6 mice, we have found that the ability to control infection is highly dependent upon the presence of HSV-1- specific CD4 ¿ and CD8 ¿ T cells, with the principal role being played by CD8 ¿ T cells expressing cytolytic function and able to synthesize interferon-gamma (IFN-_/). The ability to express CTL function was intimately linked with the increased expression of the IL-2 receptor c_-chain, CD25. This observation lead to the conclusion that expression of high levels of CD25 was mandatory for the expression of HSV-specific CTL activity. However, a subpopulation of CD8 ¿ T cells, present both within the draining regional lymph node and within the spleen during the early phase of the response to infection, has been identified. These cells synthesize IFN- _, following antigenic stimulation in vitro without expressing elevated levels of CD25. In all other aspects, these CD8 + T cells have all of the characteristics of activated cells, suggesting that they may represent a population of effector cells able to synthesize only cytokines rather than express perforin-dependent CTL function, or may be the direct progenitors of memory CD8 ¿ T cells. The hypothesis to be addressed is that this CD8 ¿ T cell subpopulation represents a lineage of cells able to enter directly into the memory pool without proceeding through the full activation program to attain CTL function. Five specific aims will be studied. In Aim 1, the acquisition of in vivo cytolytic and cytokine synthetic functions of the CD8 ¿ T cell subpopulations will be analyzed in detail throughout the course of the initial response to infection. Also, defined CD8 ¿ T cells will be transferred to recipient animals, and the functions of the progeny determined. In Aim 2, the ability of this subpopulation to contribute to long-term memory will be assessed by adoptive transfer into appropriate recipient mice. This ability will be compared directly with "authentic" memory CD8 ¿ T cells obtained from long-term convalescent mice. Aim 3 will address the activation status and function of the distinct CD8 ¿ T cell subpopulations using a newly developed transgenic model, through the analysis of important signaling mediators, and the ability of the cells to persist as determined by measuring the percentage of apoptotic cells and the expression of anti-apoptotic molecules. Aim 4 will determine the phenotypic characteristics of the distinct CD8 ¿ T cells to understand the molecular basis for differences in the migratory patterns in vivo. Aim 5 will address the role of different cytokine species in the clonal expansion and differentiation of the distinct CD8 ¿ T cells, with focus given to the role of cytokines responsible for proliferation and differentiation. Overall, the proposal will determine whether the CD8 + 0D25 neg T cells contribute to memory, are a distinct subpopulation of effector cells with unique characteristics, or a developmental dead end. Greater insight into CD8 T cell biology will result from these studies.