Regulation of central tolerance and Treg development by recirculating Treg

通过再循环 Treg 调节中枢耐受和 Treg 发育

基本信息

批准号：
10615598
负责人：
Michael Archibald Farrar
金额：
$ 38.75万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615598
关键词：
Adult Affect Age Antigen-Presenting Cells Antigens Autoimmunity Back Biological Cell Count Cell Density Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Clonal Deletion Cytolysis Development Disease Effector Cell Ensure Equilibrium FOXP3 gene Growth Heterogeneity Homeostasis Human Immune Immune Tolerance Immune response Immune system Immunity Immunologic Surveillance Impairment Infection Life Maintenance Mediating Mus Organ Output Perinatal Peripheral Play Population Process Regulation Regulatory T-Lymphocyte Role Self Tolerance Site System T cell receptor repertoire sequencing T-Cell Development T-cell diversity T-cell receptor repertoire TNFSF10 gene TNFSF6 gene Testing Thymic epithelial cell Thymus Gland Time autoreactive T cell autoreactivity central tolerance cross reactivity effector T cell experimental study immunopathology immunoregulation mouse model novel pathogen perforin prevent thymocyte transcription factor transcriptome sequencing transcriptomics tumor

项目摘要

PROJECT SUMMARY Effective cell-based immunity depends on two major systems: (i) the ability to generate a diverse TCR repertoire capable of recognizing antigens from previously unencountered pathogens, and (ii) the ability to discriminate between self- and non-self-antigens and prevent autoimmunity. Inappropriate balance between these two systems causes a variety of disease states including ineffective tumor immune surveillance and poor pathogen clearance due to gaps in the TCR repertoire, or the onset of autoimmunity and off target immunopathology during infection. Autoimmunity can be curtailed by deleting autoreactive TCRs or diverting them into the Treg lineage in the thymus. However, given the high degree of cross-reactivity of TCRs this process cannot be truly efficient at removing all self-reactive TCRs as this would remove much of the potential diversity of the conventional TCR repertoire, thereby impairing immunity to pathogens. Thus, a key biological question is how thymic selection functions to balance protection against autoimmunity while providing effective immunity against pathogens. We hypothesize that a unique population of thymic recirculating Treg cells (RT-Treg) act as a rheostat to decrease the stringency of selection once peripheral Treg cell tolerance is established, thereby allowing for a more diverse and pathogen-reactive conventional immune system. This will be examined in two specific aims: Aim 1: Define RT-Treg heterogeneity and functional consequences of RT-Treg accumulation. Aim 2: Identify the mechanisms by which RT-Treg cells affect immune repertoires and mTEC numbers. The proposed experiments will elucidate the role that RT-Treg play in governing the stringency of central tolerance, both promoting effector cell diversity and ensuring maintenance of self-tolerance by Treg cells.

项目概要有效的细胞免疫取决于两个主要系统：(i) 产生多样化 TCR 的能力能够识别来自以前未遇到的病原体的抗原的库，以及（ii）区分自身和非自身抗原并预防自身免疫。之间不适当的平衡这两个系统会导致多种疾病状态，包括无效的肿瘤免疫监视和不良的免疫功能。由于 TCR 库的缺陷或自身免疫的发生和脱靶而导致的病原体清除感染期间的免疫病理学。可以通过删除自身反应性 TCR 或转移它们进入胸腺中的Treg谱系。然而，鉴于 TCR 的高度交叉反应性，该过程无法真正有效地消除所有自反应 TCR，因为这会消除许多潜在的传统 TCR 库的多样性，从而损害对病原体的免疫力。因此，一个关键的生物问题是胸腺选择如何发挥作用来平衡对自身免疫的保护，同时提供对病原体有有效的免疫力。我们假设胸腺再循环的独特群体 Treg 细胞 (RT-Treg) 充当变阻器，降低外周 Treg 细胞选择的严格性建立了耐受性，从而允许更加多样化和对病原体具有反应性的常规免疫系统。这将在两个具体目标中进行检验：目标 1：定义 RT-Treg 异质性和 RT-Treg 积累的功能后果。目标 2：确定 RT-Treg 细胞影响的机制免疫库和 mTEC 编号。拟议的实验将阐明 RT-Treg 在控制中央耐受性的严格性，既促进效应细胞多样性又确保维持 Treg 细胞的自我耐受。