Immunologic mechanisms that prevent autoimmunity

预防自身免疫的免疫机制

基本信息

批准号：
10265652
负责人：
HARVEY CANTOR
金额：
$ 40.78万
依托单位：
DANA-FARBER CANCER INST
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：
2020-07-06 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265652
关键词：
Affect American Antigens Autoimmune Autoimmune Diseases Autoimmunity Binding Birth CD4 Positive T Lymphocytes CD44 gene CD8 receptor CD8-Positive T-Lymphocytes CD8B1 gene Cell Lineage Cells Cellular Stress Centers for Disease Control and Prevention (U.S.)ChIP-seq Child Chronic Clone Cells Cloning Complex Development Diagnostic Disease Disease Progression Disease model Dissection Elderly Elements Eragrostis Foundations Genes Genetic Heat shock proteins IL2RB gene Immunologics Infection Investigation Knock-in Knock-in Mouse Ligands Maintenance Measurement Mediating Modeling Molecular Molecular Analysis Mus Pathogenicity Pathway interactions Peptides Point Mutation Pre-Clinical Model Prevalence Property Qa-1 Antigen Regulatory Pathway Regulatory T-Lymphocyte Rheumatoid Arthritis Self Tolerance Shapes Signal Transduction Stress Surface T-Cell Antigen Receptor Specificity T-Cell Receptor T-Lymphocyte T-cell receptor repertoire Testing Tetanus Helper Peptide Therapeutic Thymus Gland Triad Acrylic Resin Up-Regulation autoreactivity base defined contribution design effector T cell insight long term memory man mouse model nanoparticle novel therapeutic intervention prevent programs receptor response systemic autoimmune disease transcription factor transcriptome

项目摘要

PROJECT SUMMARY We have identified a subset of CD8+ cells programmed to inhibit activation and expansion of helper T (TH) cells through recognition of the class Ib MHC molecule Qa-1 (HLA-E in man). Mice that express a Qa-1 point mutation that disrupts binding of Qa-1 to the TCR/CD8 co-receptor of Treg develop dysregulated TFH responses and die of systemic autoimmune disease 9-12m after birth. Regulatory activity is mediated by <5% of CD8 T cells that express a diagnostic triad of surface receptors. We have also shown that the Helios transcription factor (TF) stabilizes the CD8 Treg genetic program and have recently identified the highly restricted T-cell receptor (TCR) repertoire that may mediate Ag-specific recognition by CD8 Treg. We use these findings to trace the development of this regulatory CD8 lineage and apply these insights towards development of novel therapeutic approaches to autoimmune disease. We propose here to test the premise that Qa-1-restricted CD8 Treg represent a unique regulatory lineage of CD8 cells that express a Helios-dependent genetic program and a restricted set of TCR specific for Qa-1/HA-E-associated self-peptides. In Aim 1, we will define the contribution of the TCR to intrathymic CD8 Treg selection and differentiation using Ag-specific TCR knock-in (KI) and retrogenic mice that express a TCR specific for Qa-1-restricted self-peptides. This analysis will also allow dissection of the molecular requirements for thymic selection and differentiation of class Ib MHC-dependent CD8+ Treg. Single-cell transcriptome analysis will be used to define the relationship between TCR specificity for Qa-1–peptide ligands and shaping of the lineage-specific genetic program of Ag-specific CD8 Treg. In Aim 2, we will define the contribution of the Helios TF to thymic and post-thymic differentiation of CD8 Treg. This approach will entail measurement of the impact of specific deletion of Helios at defined stages of Ag-specific CD8 Treg differentiation. The results from these studies and SA1 will provide a foundation for investigation of the interaction between Ag-specific CD8 Treg and target cells in disease settings (Aim 3). Here we will define the inhibitory interaction between Ag-specific CD8+ Treg and its target cells. Since Helios-dependent expression of NKG2D costimulatory receptors may be essential to CD8 Treg signaling, we will characterize the contribution of this costimulatory receptor to CD8 Treg activation by stress-associated Qa-1–Hsp60 and NKG2D ligands (NKG2D- L). Insight into this interaction will be applied to the design of nanoparticle-based therapeutic approaches to autoimmune disease.

项目摘要我们已经确定了一个编程的CD8+细胞的子集，以抑制辅助者T的激活和扩展（Th）通过识别IB类MHC分子QA-1（人为HLA-E）的细胞。表达QA-1的小鼠点突变会破坏QA-1与Treg的TCR/CD8共受体的结合发生了失调的TFH 出生后9-12m的全身自身免疫性疾病的反应和死亡。调节活动介导<5％表达表面受体的诊断三合会的CD8 T细胞。我们还表明了Helios 转录因子（TF）稳定CD8 Treg遗传程序，并最近确定了高度受限制的T细胞受体（TCR）曲目可能介导CD8 Treg介导Ag特异性识别。我们使用这些发现是为了追踪该法规CD8谱系的发展，并将这些见解应用于开发自身免疫性疾病的新型治疗方法。我们在这里提议测试QA-1限制的CD8 Treg代表独特的调节的前提 CD8细胞的谱系表达了依赖Helios的遗传程序和一组受限的TCR。 QA-1/HA-E相关的自肽。在AIM 1中，我们将定义TCR对胸膜CD8的贡献使用Ag特异性TCR敲入（Ki）和表达TCR的后源性小鼠的Treg选择和分化特定于QA-1限制的自肽。该分析还将允许解剖分子需求用于胸腺选择和分化IB MHC依赖性CD8+ Treg。单细胞转录组分析将用于定义QA-1肽配体的TCR特异性与成型之间的关系 Ag特异性CD8 Treg的谱系特异性遗传程序。在AIM 2中，我们将定义 CD8 Treg的胸腺和胸腺胸膜后分化。这种方法将需要测量 Helios在Ag特异性CD8 Treg分化的定义阶段的特定缺失的影响。这些研究的结果和SA1将为互动的投资提供基础在疾病环境中的Ag特异性CD8 Treg和靶细胞之间（AIM 3）。在这里，我们将定义抑制作用 Ag特异性CD8+ Treg与其靶细胞之间的相互作用。由于NKG2D的Helios依赖性表达共刺激接收器可能对CD8 Treg信令至关重要，我们将表征这一点的贡献通过应力相关的QA-1 – HSP60和NKG2D配体（NKG2D- L）。对这种相互作用的洞察力将应用于基于纳米颗粒的治疗方法的设计自身免疫性疾病。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Stable inhibitory activity of regulatory T cells requires the transcription factor Helios.

DOI：
10.1126/science.aad0616
发表时间：
2015-10-16
期刊：
Science (New York, N.Y.)
影响因子：
0
作者：
Kim HJ;Barnitz RA;Kreslavsky T;Brown FD;Moffett H;Lemieux ME;Kaygusuz Y;Meissner T;Holderried TA;Chan S;Kastner P;Haining WN;Cantor H
通讯作者：
Cantor H

Physiological induction of regulatory Qa-1-restricted CD8+ T cells triggered by endogenous CD4+ T cell responses.

DOI：
10.1371/journal.pone.0021628
发表时间：
2011
期刊：
PloS one
影响因子：
3.7
作者：
Varthaman A;Clement M;Khallou-Laschet J;Fornasa G;Gaston AT;Dussiot M;Caligiuri G;Cantor H;Kaveri S;Nicoletti A
通讯作者：
Nicoletti A

Regulatory T cells subdue an autoimmune disease.

调节性 T 细胞可抑制自身免疫性疾病。