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Autoreactive CD4 T cells in healthy mice

健康小鼠的自身反应性 CD4 T 细胞

基本信息

批准号：
10170262
负责人：
LESZEK IGNATOWICZ
金额：
$ 38.99万
依托单位：
GEORGIA STATE UNIVERSITY
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：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10170262
关键词：
Ablation Agonist Antigen Receptors Antigen-Presenting Cells Autoantigens Autoimmune Diseases Autoimmunity Bar Codes Bypass CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cells Chromatin Development Devices Diphtheria Toxin Disabled Persons Epigenetic Process Gene Targeting Genomics Homeostasis Human Immune response Individual Infection Lead MHC Class I Genes MHC Class II Genes Maintenance Malignant Neoplasms Microfluidics Modeling Mus Organ Pathogenicity Peptides Peripheral Protocols documentation Receptor Cell Regulatory T-Lymphocyte Research Rest Role Self Tolerance Specificity Stromal Cells System T-Lymphocyte T-Lymphocyte Subsets TCR Activation Testing Therapeutic Thymus Gland Tissues Transposase autoreactive T cell autoreactivity central tolerance high throughput analysis lymphoid organ novel therapeutics peripheral tolerance prevent reconstruction response single-cell RNA sequencing thymocyte transcriptome

项目摘要

In the thymus, central tolerance should eliminate the majority of immature T cells that express autoreactive, pathogenic antigen receptors (αβTCRs). However, an unknown number of autoreactive cells escape deletion or commit to immunosuppressive, regulatory linage (Tregs). Tregs control peripheral tolerance and sustain dormancy of potentially autoreactive T cells. However, mice and humans with disabled Tregs rapidly develop multiorgan autoimmunity and die young, manifesting polyclonal activation of almost all CD4+ clones. Thus, we hypothesized that the number of autoreactive clones embedded in the peripheral repertoire can be much higher (i.e. over one-third of all CD4+ cells) as compared to what is currently anticipated. In Specific Aim 1, we will examine how the intrathymic expression of different self-peptides supports or prevents an escape of autoreactive T cells from central tolerance. This approach will document that potentially self-reactive CD4+ clones commonly trespass to lymphoid organs of B6 mice as quiescent cells. Next, we will test these cells ex vivo responses to a known set of self-peptides naturally presented by mouse Ab molecules to determine if these clones are triggered by ubiquitous or specific autoantigens. In Specific Aim 2, we will investigate why mice expressing single autoantigen across the body have main autoimmunity manifestation in specific organs and examine the role of non-classical CD4+ T cells in autoimmunity in this model. In Aim 3 we will use a new single-cell RNA seq system from 10X Genomics, to examine in individual CD4+ cells their transcriptomes and native αβTCRs to identify genes targeted by Tregs in potentially autoreactive cells to keep them dormant and prevent autoimmunity. Overall, this application will revisit the relative importance of various mechanisms of tolerance in the maintenance of homeostasis to self- antigens and can reveal new mechanisms of how Tregs control self-reactivity.

在胸腺中，中枢耐受应该会消除大部分未成熟的T细胞