Non-deletional CD8 T cell self-tolerance

非缺失 CD8 T 细胞自我耐受

基本信息

批准号：
10688010
负责人：
STEPHEN C JAMESON
金额：
$ 35.9万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10688010
关键词：
ATAC-seq Acceleration Acute Address Alopecia Areata Antigens Apoptosis Apoptotic Autoantigens Autoimmune Autoimmune Diseases Autoimmunity Automobile Driving Avidity Biological Models CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Death Cells Chromatin Clinical Clonal Deletion Data Defect Environment Exposure to Frequencies Gene Expression Genes Health Human Immune system Immunization Immunotherapy In Vitro Inbred Mouse Infection Infectious Skin Diseases Inflammation Knowledge Laboratory mice Left Maintenance Mediating Microbe Minnesota Minor Modeling Molecular Mus Mutate Normal tissue morphology Pathway interactions Peripheral Phenotype Physiological Play Psoriasis Recording of previous events Regulatory T-Lymphocyte Reporting Role Self Tolerance Skin T cell anergy T cell response T-Cell Activation T-Lymphocyte Testing Universities Vitiligo Wild Type Mouse Work anergy autoreactive T cell autoreactivity cancer immunotherapy exhaustion experience immunopathology improved in vivo melanocyte melanoma microbial mouse model prevent recruit response transcriptome sequencing

项目摘要

Summary Self-tolerance requires that auto-reactive T cells either be physically eliminated, sequestered away from self- antigen and/or incapacitated in their response to normal tissues. There have been many studies on deletional tolerance and “ignorance” of self-antigens among CD8+ T cells, but much less is understood about how anergy regulates that response T cell response. Studies on this issue are especially urgent, since recent data suggest that anergy is the prevalent mechanism of CD8+ T cell self-tolerance in humans – but we lack appropriate mouse models to investigate this critical mechanism. We address this issue with studies on mouse CD8+ T cells that recognize the normal melanocyte antigens, which we demonstrate are tolerant through a form of cell- intrinsic anergy. In Aim 1, we explore the basis for this anergy, building on preliminary studies to investigate whether self-reactive CD8+ T cells are prone to apoptotic cell death following activation and using RNA-seq and ATAC-seq approaches to define the gene expression and chromatin accessibility status of anergic versus functional CD8+ T cells. In Aim 2, we test the reversibility of anergy, evaluating the role of continued self- antigen exposure in maintaining this state, and we formally explore the potential role of Treg, as a cell-extrinsic mechanism of inducing or perpetuating CD8+ T cell anergy. Finally, in Aim 3, we examine how the lack of physiological exposure to normal skin infections and inflammation may compromise the value of current mouse models for induction of autoimmune vitiligo (destruction of normal melanocytes following breakdown of CD8+ T cell self-tolerance to melanocyte antigens). Our studies utilize models of acute skin inflammation and infection, and also inbred mice that have been naturally infected with normal mouse microbes (“normal microbial experience” mice, also called “dirty” mice) – a model which we developed at the University of Minnesota to enhance mouse studies with improved relevance to humans.

概括自我耐受要求自身反应性 T 细胞要么被物理消除，要么被隔离，远离自我耐受。抗原和/或对正常组织的反应能力丧失已有许多关于缺失的研究。 CD8+ T 细胞对自身抗原的耐受性和“无知”，但对于无反应性如何产生的了解却少之又少。由于最近的数据表明，对这个问题的研究尤其紧迫。能量是人类 CD8+ T 细胞自我耐受的普遍机制 - 但我们缺乏适当的我们通过对小鼠 CD8+ T 的研究来解决这个问题。识别正常黑素细胞抗原的细胞，我们证明这些细胞通过某种形式的细胞- 在目标 1 中，我们在初步研究的基础上探索了这种无能的基础。自我反应性 CD8+ T 细胞在激活和使用 RNA-seq 后是否容易发生细胞凋亡和 ATAC-seq 方法来定义无能与无能与无能的基因表达和染色质可及性状态在目标 2 中，我们测试了功能性 CD8+ T 细胞的可逆性，评估持续自我修复的作用。抗原暴露维持这种状态，我们正式探索 Treg 作为细胞外源性的潜在作用最后，在目标 3 中，我们研究了诱导或维持 CD8+ T 细胞无反应性的机制。正常皮肤感染和炎症的生理暴露可能会损害当前小鼠的价值诱导自身免疫性白癜风的模型（CD8+ T 分解后正常黑素细胞的破坏）细胞对黑素细胞抗原的自我耐受）。我们的研究利用急性皮肤炎症和感染模型，以及自然感染正常小鼠微生物的近交小鼠（“正常微生物经验“老鼠，也称为“肮脏”老鼠）——我们在明尼苏达大学开发的模型加强小鼠研究，提高与人类的相关性。