Non-deletional CD8 T cell self-tolerance

非缺失 CD8 T 细胞自我耐受

• 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
• 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

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.

总结 自我耐受需要自身反应性T细胞被物理消除，远离自我免疫， 抗原和/或丧失对正常组织的应答。有很多关于删除的研究 免疫耐受和“无知”的自身抗原的CD 8 + T细胞，但少得多的是了解如何无能 调节T细胞的反应。对这一问题的研究尤为紧迫，因为最近的数据表明， 无反应性是人类CD 8 + T细胞自我耐受的普遍机制-但我们缺乏适当的 小鼠模型来研究这一关键机制。我们通过对小鼠CD 8 + T细胞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是耐受的， 内在无反应性在目标1中，我们探索了这种无反应性的基础，建立在初步研究的基础上， 自身反应性CD 8 + T细胞在活化后是否倾向于凋亡性细胞死亡，并使用RNA-seq 和ATAC-seq方法来确定无反应性与 功能性CD 8 + T细胞在目标2中，我们测试了无反应性的可逆性，评估了持续自我调节的作用， 抗原暴露在维持这种状态，我们正式探讨了Treg的潜在作用，作为细胞外 诱导或维持CD 8 + T细胞无能的机制。最后，在目标3中，我们研究了缺乏 生理性暴露于正常皮肤感染和炎症可能损害当前小鼠的价值， 诱导自身免疫性白癜风的模型（CD 8 + T细胞破坏后正常黑素细胞的破坏 细胞对黑素细胞抗原的自身耐受性）。我们的研究利用急性皮肤炎症和感染的模型， 以及已经被正常小鼠微生物（“正常微生物”）自然感染的近交系小鼠 经验”小鼠，也称为“脏”小鼠）-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。