Differentiation and function of intestinal tissue-resident memory T cells

T细胞在清除病原体方面起着至关重要的作用，而记忆T细胞的产生是保护机体免受二次感染的重要组成部分。记忆T细胞可以根据它们的位置分为两类，一类是能够在全身循环的细胞，另一类是滞留在组织中的细胞，准备对二次感染做出快速反应。组织驻留的记忆T细胞(Trm)细胞保留在组织中，感染消除后不会被循环细胞补充。循环中的T细胞通常不足以预防二次感染；因此，确定Trm细胞是如何产生的并随着时间的推移保持其功能是非常有意义的。只有一小部分微生物需要突破粘膜表面才能引发疾病。适应性免疫细胞在大型、复杂的组织中定位病原体并在病原体扩散到更深的组织之前将其消除的能力是保护性免疫的必要组成部分。我们使用肠道病原体假结核耶尔森菌的感染来检测感染过程中病原体特异性的CD8+Trm，利用这个模型，我们发现肠道Trm细胞具有显著的表型异质性，整合素CD103的表达定义了这些群体。T细胞与肠道组织内感染区域的接近调节Trm的分化，炎症和转录因子STAT4的激活导致CD103 Trm细胞数量增加。这项建议将确定调节CD103 Trm亚群分化和维持的潜在机制。我们已经证明了CD103 Trm细胞在初次感染期间控制病原体复制的关键作用，并开发了新的工具来分析二次感染期间Trm亚群之间的分工。这些发现将解决我们对Trm细胞在继发感染期间控制肠道定植的功能的认识上的一个根本空白。此外，目前尚不清楚Trm亚群本身是否足以提供保护，我们将确定Trm细胞的完整组合是否是强大免疫所必需的。这项工作将确定最大限度地增加Trm细胞的数量和持久性的策略，这是任何针对粘膜病原体的成功疫苗接种策略的重要组成部分。

T cells play a critical role eliminating pathogens and the generation of memory T cells is an important component in protection from secondary infection. Memory T cells can be divided into two groups based on their location, those that are capable of circulating throughout the body and those that are lodged in tissues, poised to respond rapidly to secondary infection. Tissue-resident memory T cells (Trm) cells remain in the tissue and are not replenished by circulating cells after infection is resolved. Circulating T cells are often not sufficient to protect from secondary infection; therefore, it is of significant interest to determine how Trm cells are generated and maintain their function over time. Only a small number of microbes need to breach the mucosal surface to initiate disease. The ability of adaptive immune cells to locate pathogens in large, complex tissues and eliminate them before they disseminate to deeper tissues is a necessary component of protective immunity. We have used infection with the intestinal pathogen Yersinia pseudotuberculosis to examine pathogen-specific CD8+ Trm during infection, and using this model we have uncovered significant phenotypic heterogeneity in intestinal Trm cells, with expression of the integrin CD103 defining these populations. Proximity of T cells to areas of infection within the intestinal tissue regulates Trm differentiation, with inflammation and activation of the transcription factor STAT4 leading to increased numbers of CD103 Trm cells. This proposal will identify the underlying mechanisms that regulate the differentiation and maintenance of the CD103 Trm subset. We have already shown a critical role for CD103 Trm cells in controlling pathogen replication during primary infection, and we have developed new tools to analyze the division of labor between Trm subsets during secondary infection. These findings will address a fundamental gap in our knowledge regarding the function of Trm cells in controlling intestinal colonization during secondary infection. Additionally, it is currently unclear whether either Trm subset alone is sufficient to confer protection, and we will determine if the full complement of Trm cells is necessary for robust immunity. This work will identify strategies to maximize the number and persistence of Trm cells, an important component of any successful vaccination strategy to target mucosal pathogens.