Biology and Function of anti-HSV CD8 T Cells

抗 HSV CD8 T 细胞的生物学和功能

• 批准号: 7219966
• 负责人: STEPHEN ROBERT JENNINGS
• 金额: $ 28.95万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7219966
• 关键词: Acute; Address; Adoptive Transfer; Affect; Animals; Antigens; Apoptosis; Apoptotic; Biology; C57BL/6 Mouse; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Adhesion Molecules; Cell Lineage; Cells; Cellular biology; Characteristics; Clonal Expansion; Cutaneous; Cytokine Receptors; Cytolysis; Detection; Development; Effector Cell; Elements; Endoribonucleases; Epitopes; Event; Exposure to; Fibroblasts; Frequencies; Generations; Herpesvirus 1; IL2RA gene; IL2RG gene; Image Analysis; Immune response; Immunologic Memory; In Vitro; Infection; Infection Control; Interferon Type II; Interferons; Interleukin 2 Receptor; Interleukin-15; Interleukin-2; Interleukin-4; Interleukin-7; Label; Lead; Life; Link; Longevity; Lymphocyte-Specific p56LCK Tyrosine Protein Kinase; Maintenance; Measures; Mediator of activation protein; Memory; Microscopic; Modeling; Molecular; Mouse Protein; Mus; Numbers; Pancreatic ribonuclease; Pattern; Peptides; Phase; Phosphotransferases; Physiologic pulse; Play; Population; Protein Tyrosine Kinase; Proteins; Pulse taking; Research Personnel; Ribonucleases; Role; Signal Transduction; Sorting - Cell Movement; Source; Spleen; Staining method; Stains; T memory cell; T-Cell Depletion; T-Lymphocyte; Transgenic Model; Transgenic Organisms; Virus Diseases; base; chemokine receptor; concept; congenic; cytokine; functional status; in vivo; insight; long term memory; lymph nodes; mouse model; perforin; progenitor; programs; promoter; protein expression; receptor expression; response; study characteristics

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.

目前关于长期T细胞记忆的建立和维持的概念提出，记忆T细胞是 来源于小的;存活的效应T细胞亚群。使用皮肤HSV-1感染模型， 在C57 BL/6小鼠中，我们发现控制感染的能力高度依赖于HSV-1的存在。 特异性CD 4 <$T细胞和CD 8 <$T细胞，主要由表达细胞溶解功能的CD 8 <$T细胞发挥作用， 能够合成干扰素-γ（IFN-γ）。表达CTL功能的能力与细胞免疫功能密切相关。 IL-2受体c_链，CD 25的表达增加。这一观察导致的结论是，表达的 高水平的CD 25对于HSV特异性CTL活性的表达是必需的。然而，CD 8亚群 T细胞，存在于引流区域淋巴结内和脾脏内，在淋巴结转移的早期阶段， 对感染的反应，已经确定。这些细胞在体外抗原刺激后合成IFN-γ， 表达高水平的CD 25。在所有其他方面，这些CD 8 + T细胞具有活化的T细胞的所有特征。 细胞，这表明它们可能代表了一群效应细胞，只能合成细胞因子，而不能合成细胞因子。 表达穿孔素依赖性CTL功能，或者可能是记忆性CD 8 + T细胞的直接祖细胞。假设， 这一CD 8 T细胞亚群代表了一个能够直接进入记忆的细胞谱系， 池，而无需通过完整的激活程序来实现CTL功能。将研究五个具体目标。在 目的1，获得体内CD 8 ~+ T细胞亚群的细胞溶解和细胞因子合成功能， 详细分析了整个感染初期的反应过程。此外，定义的CD 8 <$T细胞将是 转移到受体动物中，并确定后代的功能。在目标2中，该亚群的能力 将通过过继转移到适当的受体小鼠中来评估对长期记忆的贡献。这个技能将 直接与从长期恢复期小鼠中获得的“真实”记忆CD 8 <$T细胞进行比较。目标3将 使用新开发的方法解决不同CD 8 <$T细胞亚群的激活状态和功能， 转基因模型，通过分析重要的信号介质，和细胞的能力，坚持作为 通过测量凋亡细胞的百分比和抗凋亡分子的表达来确定。目标4将 确定不同的CD 8 <$T细胞的表型特征，以了解差异的分子基础， 体内的迁移模式目的5将阐明不同细胞因子种类在克隆扩增中的作用， 不同的CD 8 T细胞的分化，重点是细胞因子的作用，负责增殖和 分化总的来说，该提案将确定CD 8 + 0 D25阴性T细胞是否有助于记忆，是否是一种免疫调节剂。 具有独特特征的效应细胞的不同亚群，或发育的死胡同。更深入地了解 CD 8 T细胞生物学将从这些研究中产生。