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

基本信息

批准号：
10684315
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
项目类别：
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/10684315
关键词：
Adipose tissue Area Biological Models Biological Process CD8-Positive T-Lymphocytes CD8B1 gene Cell Maintenance Cells Cellular biology Chromatin Complement Complex Disease Epigenetic Process Gene Expression Profile Generations HIV Heterogeneity Histone Acetylation Immune Immune response Immunity Impairment Individual Infection Inflammation Inflammatory 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 cell differentiation T cell response T memory cell T-Lymphocyte T-Lymphocyte Subsets Testing Time Tissue Differentiation Tissues Transcriptional Activation Translating Vaccination Work design enteric pathogen gut colonization human pathogen insight interest mucosal vaccine pathogen prevent recruit response secondary infection single-cell RNA sequencing tissue resident memory T cell tool vaccination strategy vaccine efficacy

项目摘要

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细胞起着消除病原体的关键作用，并且记忆T细胞的产生是保护次感染的重要组成部分。记忆T细胞可以根据其位置分为两组，这些位置能够在整个身体中循环的细胞，以及在组织中循环的那些位置，这些人能够迅速对继发感染做出迅速反应。组织驻留的记忆T细胞（TRM）细胞保留在组织中，并且在感染后不被循环细胞补充。循环T细胞通常不足以防止继发感染。因此，确定如何生成TRM细胞并随着时间的推移维护其功能是引人注目的。只有少数微生物需要破坏粘膜表面才能引发疾病。自适应免疫细胞在大型复杂组织中定位病原体并在将它们传播到更深的组织之前消除它们的能力是保护性免疫的必要组成部分。我们已经将感染与肠道病原体耶尔森氏菌病原体一起检查感染期间病原体特异性的CD8+ TRM，并且使用该模型，我们发现了肠道TRM细胞中的显着表型异质性，并表达整联蛋白CD103，确定了这些群体。 T细胞与肠道组织内感染区域的接近性调节TRM分化，转录因子STAT4的炎症和激活导致CD103 TRM细胞数量增加。该建议将确定调节CD103 TRM子集的分化和维护的基本机制。我们已经显示出CD103 TRM细胞在控制原发性感染过程中的病原体复制中的关键作用，并且我们开发了新的工具来分析继发性感染期间TRM亚群之间的劳动分裂。这些发现将解决我们有关TRM细胞在控制继发感染期间控制肠道定植功能的知识方面的基本差距。此外，目前尚不清楚单独的任何一个TRM子集是否足以提供保护，我们将确定TRM细胞的完整补体是否对于稳健的免疫力是必需的。这项工作将确定最大化TRM细胞的数量和持久性的策略，这是任何成功疫苗接种策略以靶向粘膜病原体的重要组成部分。