Regulation of T cell immunity within the female reproductive tract

描述(申请人提供)：女性生殖器粘膜是感染艾滋病毒的主要途径。这项建议将解决有关女性生殖道内T细胞免疫生物学知识的重大空白。基本问题，包括记忆CD8和CD4T细胞的分化、维持、贩运、功能和对保护的贡献，将在一个高通量、易驯化的小鼠模型中解决。对记忆T细胞分化状态和功能的体外分析将得到静态和活体成像的补充，以得出T细胞免疫生物学和APC/抗原在这个复杂器官系统内运输的更完整的解剖图像。最近发现的局部记忆T细胞功能的潜在机制，包括增强快速外周T细胞招募和激活局部先天免疫系统的能力，将被定义。通过女性生殖道不同间隔的记忆T细胞再循环模式将被定义为异种共生。将评估局部和外周记忆T细胞群体对预防生殖器病毒再次挑战的贡献。这些研究将为T细胞疫苗的开发提供信息，这种疫苗通过提供对该部位细胞免疫的调节、功能和保护机制的新见解，在女性生殖道内暴露时迅速拦截艾滋病毒。

DESCRIPTION (provided by applicant): The female genital mucosa is a major route of infection for HIV. This proposal will address significant gaps in knowledge regarding T cell immunobiology within the female reproductive tract. Fundamental issues, including memory CD8 and CD4 T cell differentiation, maintenance, trafficking, function, and contribution to protection will be addressed in a high-throughput tractable mouse model. Ex vivo analyses of memory T cell differentiation state, and function will be complemented by static and intravital imaging to yield a more complete anatomic picture of T cell immunobiology and APC/antigen trafficking within this complex organ system. Mechanisms underlying recently discovered functions of local memory T cells, including the ability to potentiate rapid peripheral T cell recruitment and activate the local innate immune system, will be defined. Memory T cell recirculation patterns through various compartments of the female reproductive tract will be defined by parabiosis. Contributions of local and peripheral memory T cell populations to protection against genital viral re-challenge will be assessed. These investigations will inform the development of T cell vaccines that rapidly intercept HIV upon exposure within the female reproductive tract by providing new insight into the regulation, function and protective mechanisms of cellular immunity at this site.