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

• 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
• 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

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.

项目摘要 有效的基于细胞的免疫力取决于两个主要系统：（i）产生多种TCR的能力 能够识别以前未经病原体的抗原的曲目，以及（ii） 区分自我和非自身抗原并防止自身免疫性。之间的不适当平衡 这两个系统导致各种疾病状态，包括无效的肿瘤免疫监测和差 病原体清除由于TCR曲目中的间隙或自身免疫的发作和关闭目标而引起的 感染过程中的免疫病理学。可以通过删除自动反应性TCR或转移自身免疫性来减少自身免疫性 它们进入胸腺中的Treg谱系。但是，鉴于TCR的高度交叉反应性 过程不能真正有效地消除所有自我反应性TCR，因为这将消除许多潜力 常规TCR曲目的多样性，从而损害了对病原体的免疫力。因此，关键的生物学 问题是胸腺选择如何在提供自身免疫性的情况下取得平衡的功能 有效抵抗病原体的免疫力。我们假设胸腺循环的独特群 treg细胞（RT-Treg）充当变阻器，可降低一旦外围treg细胞的选择严格 建立了公差，从而允许更加多样化和病原体反应性传统 免疫系统。这将在两个具体目的中进行检查：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 免疫曲目和MTEC数字。提出的实验将阐明RT-Treg在 管理中央耐受性的严格性，既促进效应细胞多样性又确保维护 Treg细胞自耐受。