Differentiation and function of intestinal tissue-resident memory T cells

肠道组织驻留记忆T细胞的分化和功能

• 批准号: 10466863
• 负责人: Tessa Bergsbaken
• 金额: $ 38.76万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10466863
• 关键词: Address; Adipose tissue; Area; Biological Models; Biological Process; Biology; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Chromatin; Complement; Complex; Disease; Epigenetic Process; Gene Expression Profile; Generations; HIV; Heterogeneity; Histone Acetylation; Immune; Immune response; Immunity; Impairment; Individual; Infection; Inflammation; Integrins; Interleukin-12; Intestines; Invaded; Knowledge; Laboratories; Lamina Propria; Liver; Location; Maintenance; Mediating; Memory; Metabolic; Metabolism; Microbe; Modeling; Mucosal Immunity; Mucous Membrane; Mus; Mycobacterium tuberculosis; Pasteurella pseudotuberculosis; Phenotype; Play; Population; Primary Infection; Proliferating; Regulation; Role; STAT4 gene; STAT4 protein; Secondary to; Signal Transduction; Surface; T memory cell; T-Lymphocyte; Testing; Time; Tissues; Transcriptional Activation; Translating; Vaccination; Work; base; design; enteric pathogen; gut colonization; human pathogen; insight; interest; mucosal vaccine; pathogen; prevent; recruit; response; secondary infection; single-cell RNA sequencing; tool; vaccination strategy; vaccine efficacy

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.

T 细胞在消除病原体方面发挥着关键作用，记忆 T 细胞的产生是防止继发感染的重要组成部分。记忆T细胞根据其位置可分为两组，一组能够在全身循环，一组驻留在组织中，准备对继发感染做出快速反应。组织驻留记忆 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 T 细胞通常不足以防止继发感染；因此，确定 Trm 细胞如何产生并随着时间的推移维持其功能具有重要意义。只有少数微生物需要突破粘膜表面来引发疾病。适应性免疫细胞在大型复杂组织中定位病原体并在其传播到更深组织之前将其消除的能力是保护性免疫的必要组成部分。我们利用肠道病原体假结核耶尔森氏菌的感染来检查感染过程中病原体特异性 CD8+ Trm，并使用该模型，我们发现了肠道 Trm 细胞中显着的表型异质性，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可调节 Trm 分化，炎症和转录因子 STAT4 的激活导致 CD103 Trm 细胞数量增加。该提案将确定调节 CD103 Trm 子集分化和维持的基本机制。我们已经展示了 CD103 Trm 细胞在原发感染期间控制病原体复制中的关键作用，并且我们开发了新工具来分析继发感染期间 Trm 亚群之间的分工。这些发现将弥补我们关于 Trm 细胞在继发感染期间控制肠道定植的功能方面的知识中的根本空白。此外，目前尚不清楚单独的 Trm 子集是否足以提供保护，我们将确定 Trm 细胞的完整补充是否是强大免疫所必需的。这项工作将确定最大化 Trm 细胞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。