Defining tissue specific phenotypes that faithfully identify tissue resident memory T cells

定义忠实识别组织驻留记忆 T 细胞的组织特异性表型

基本信息

批准号：
10460129
负责人：
Milcah C Scott
金额：
$ 3.29万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-06 至 2023-07-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10460129
关键词：
Address Anatomy Autoimmune Responses Autoimmunity Awareness CD8-Positive T-Lymphocytes CD8B1 gene CRISPR/Cas technology Cell surface Disease Exhibits Flow Cytometry Future Generations Genes Genetic Transcription Graft Rejection Growth Health Heterogeneity Human Hypersensitivity Immune response Immune system Immunity Immunologic Surveillance Infection Inflammation Inflammatory Knowledge Location Maintenance Malignant Neoplasms Mediating Memory Mus Parabiosis Peripheral Phenotype Play Population Preventive vaccine Process Reporting Research Residencies Role Surface T memory cell T-Lymphocyte T-Lymphocyte Subsets Techniques Testing Tissues Vaccination Vaccines Validation Virus Diseases allergic response antiviral immunity autoimmune pathogenesis design exhaustion immunopathology innovation pathogen phenotypic biomarker prevent programs receptor response therapy development tumor vaccine development

Address Anatomy Autoimmune Responses Autoimmunity Awareness CD8-Positive T-Lymphocytes CD8B1 gene CRISPR/Cas technology Cell surface Disease Exhibits Flow Cytometry Future Generations Genes Genetic Transcription Graft Rejection Growth Health Heterogeneity Human Hypersensitivity Immune response Immune system Immunity Immunologic Surveillance Infection Inflammation Inflammatory Knowledge Location Maintenance Malignant Neoplasms Mediating Memory Mus Parabiosis Peripheral Phenotype Play Population Preventive vaccine Process Reporting Research Residencies Role Surface T memory cell T-Lymphocyte T-Lymphocyte Subsets Techniques Testing Tissues Vaccination Vaccines Validation Virus Diseases allergic response antiviral immunity autoimmune pathogenesis design exhaustion immunopathology innovation pathogen phenotypic biomarker prevent programs receptor response therapy development tumor vaccine development

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项目摘要

ABSTRACT CD8 T cells control live replicating viral infections, but most licensed vaccines do not efficiently generate protective memory CD8 T cells. Recent evidence suggests that developing vaccines that establish memory CD8 T cells may be the solution to controlling or preventing historically recalcitrant pathogens. Tissue-resident memory CD8 T cells (TRM), which occupy many tissues of the body without circulating and persist long term, have a vital role in tissue immunosurveillance. TRM are also increasingly thought to mediate allergic and autoimmune responses and transplant rejection. TRM were only recently discovered, and thus there are substantial gaps in our understanding of the mechanisms by which TRM achieve anti-viral immunity and contribute to immunopathology. If future vaccination and therapy strategies are to successfully leverage CD8 TRM for protection against pathogens or reducing immunopathology, fundamental questions on how TRM are generated and maintained in tissue need to be addressed. I recently compared the transcriptional programs of TRM populations with recirculating T cell subsets and CD8 T cell populations that transiently express the imperfect TRM marker CD69 in response to recent TCR stimulation or inflammation. I also developed an original approach and workflow to identify tissue specific TRM phenotypes. Through Aim 1 I will further expand our knowledge of shared and tissue specific CD8 TRM transcriptional and phenotypic signatures. I will also validate tissue specific phenotypes via flow cytometry, parabiosis studies, and the use of `dirty' mice that contain CD69+ T cells within the equilibrating T cell population. Through Aim 2 I will apply a CRISPR/Cas9 gene editing approach that I have established to evaluate the role of several exhaustion genes in the ontogeny, differentiation and maintenance of TRM. Further elucidation of how tissue-resident memory T-cell populations are generated and maintained in peripheral tissues and the role they play in immune responses in tissue will assist in the design of prophylactic vaccines and may also inform the development of therapies that treat intractable infections or disease.

抽象的 CD8 T细胞控制着复制病毒感染的活体，但大多数许可的疫苗无法有效产生保护性记忆CD8 T细胞。最近的证据表明，开发建立记忆CD8的疫苗 T细胞可能是控制或预防历史上顽固的病原体的解决方案。组织居民记忆CD8 T细胞（TRM），它占据了身体的许多组织而无需循环并长期持续在组织免疫监视中具有至关重要的作用。 TRM也越来越被认为介导过敏性和自身免疫反应和移植排斥。 TRM直到最近才发现，因此我们对TRM获得抗病毒免疫的机制的理解有很大的差距进行免疫病理学。如果未来的疫苗接种和治疗策略是成功利用CD8 TRM 保护病原体或减少免疫病理学，有关如何生成TRM的基本问题需要解决组织中。我最近比较了TRM的转录程序循环T细胞子集和CD8 T细胞种群的种群瞬时表达不完美的 TRM标记CD69响应最近的TCR刺激或炎症。我还开发了一种原始方法和工作流程以识别特定于组织的TRM表型。通过目标1，我将进一步扩大我们对共享和组织特异性CD8 TRM转录和表型特征。我还将验证特定于组织通过流式细胞术，抛物线研究和使用含有CD69+ T细胞的“肮脏”小鼠的使用表型平衡T细胞群。通过AIM 2，我将采用CRISPR/CAS9基因编辑方法建立以评估几个耗尽基因在个体发育，分化和维持的作用 trm。进一步阐明如何生成组织居民记忆T细胞种群外围组织及其在组织中的免疫反应中所起的作用将有助于预防性设计疫苗，还可能告知治疗顽固感染或疾病的疗法的发展。