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：
10466846
负责人：
STEPHEN C JAMESON
金额：
$ 36.44万
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/10466846
关键词：
ATAC-seq 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

ATAC-seq 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

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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.

概括自耐耐受要求自身反应性T细胞可以物理消除，隔离自我抗原和/或无能力对正常组织的反应。有许多关于缺失的研究 CD8+ T细胞中自我抗原的耐受性和“无知”，但对厌食症的理解少得多调节响应T细胞反应。关于此问题的研究特别紧急，因为最近的数据表明 Anergy是人类CD8+ T细胞自我耐受性的普遍机制 - 但我们缺乏合适的小鼠模型研究这种关键机制。我们通过小鼠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，通过一种细胞形式固有的反感。在AIM 1中，我们探索了这种不满的基础，基于初步研究以调查自我反应性CD8+ T细胞是否容易激活后凋亡细胞死亡和使用RNA-Seq 和ATAC-SEQ方法来定义厌食的基因表达和染色质可及性状态功能性CD8+ T细胞。在AIM 2中，我们测试了不反应的可逆性，评估了持续自我的作用抗原在维持这种状态中的暴露，我们正式探索Treg的潜在作用，作为细胞超支诱导或永续的CD8+ T细胞消极的机制。最后，在AIM 3中，我们研究了缺乏生理暴露于正常皮肤感染和感染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崩溃后正常黑色素细胞的破坏细胞自耐对黑素抗原）。我们的研究利用急性皮肤感染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增强小鼠研究，并改善了与人类的相关性。