Loss of Intrinsic Control in Autoimmune T Helper Cells with Signaling Variants

具有信号变异的自身免疫 T 辅助细胞失去内在控制

• 批准号: 10396864
• 负责人: JEROEN ROOSE
• 金额: $ 24.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396864
• 关键词: Address; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; B-Cell Activation; B-Lymphocytes; BLR1 gene; CD4 Positive T Lymphocytes; Cell Line; Cell physiology; Cells; Cellular Metabolic Process; Cellular biology; Data; Development; Disease; Genes; Genetic Transcription; Genetic Translation; Goals; Grant; HDAC7 histone deacetylase; Helper-Inducer T-Lymphocyte; Homeostasis; Human; Image; Immune; Immunologics; Lead; Link; MHC Interaction; Messenger RNA; Metabolic; Metabolism; Mission; Molecular; National Institute of Allergy and Infectious Disease; Pathogenicity; Pathway interactions; Patients; Peptide/MHC Complex; Peptides; Peripheral; Phenotype; Phosphorylation; Play; Production; Progress Reports; Reporting; Research; Research Personnel; Resolution; Rest; Rheumatoid Arthritis; Role; ST14 gene; Sampling; Secure; Severity of illness; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Sirolimus; Systemic Lupus Erythematosus; T cell differentiation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Time; Tissues; Translating; United States National Institutes of Health; Variant; autoreactive T cell; autoreactivity; fitness; gene function; genetic variant; improved; in vivo; innovation; innovative technologies; insight; interest; mTOR Inhibitor; mouse model; programmed cell death protein 1; programs

PROJECT SUMMARY/ABSTRACT Auto-reactive CD4+ T cells play an important role in the development of autoimmune diseases such as systemic lupus erythematosus (SLE) and are often entangled in a stimulatory loop with other immune cells. Autoantibodies that cause tissue damage and release of self-antigens lead to further spurious activation and differentiation of self-reactive CD4+ T cells. It is not known through what molecular mechanisms aberrant self-recognition can cause loss of intrinsic control in T cells. Patrolling T cells constantly encounter self-peptides (self-p/MHC) and self-recognition drives low-level, tonic signals. Since the late 1980's, tonic signals have been detected in resting T cells but the function of such signals have long remained a mystery. During 1R01AI104789 we uncovered that tonic signals dynamically control the naïve CD4+ T cell state. Tonic signals suppress spurious activation and differentiation of naïve T cells through the transcriptional induction of target genes that function as brakes. On the other hand, we also revealed that tonic signals prime the cellular activity of naïve T cells by translating other target genes that elevate the energetic and metabolic state. This second type of tonic signal is transmitted through a newly discovered tonic Rasgrp1-mTORC1 pathway and results in constitutive mRNA translation of roughly 3000 genes in resting CD4+ T cell. Tonic mTORC1 signals are surprisingly selective and robust and are aberrantly elevated by self-recognition and by a SNV (Single nucleotide variant) in Rasgrp1. T cells with a Rasgrp1Anaef variant display increased tonic-mTORC1 signals that aberrantly translate mRNA targets, spontaneously differentiate in ICOS+PD-1+CXCR5-Bcl6- T peripheral helper (TPH) cells, and cause pathogenic production of autoantibodies by B cells. These studies provide a framework to obtain molecular or mechanistic understanding of self-recognition, tonic signaling, T cell biology, and autoimmunity. Our renewal focuses on understanding how aberrant self-recognition and increased tonic Rasgrp1- mTORC1 signals can lead to altered metabolism in naïve CD4+ T cells over time and ultimately drive spurious activation and differentiation of pathogenic CD4+ T cell subsets. We will investigate the new non- canonical, tonic Rasgrp1-mTORC1 signaling pathway that we discovered (Aim 1). We will establish the in vivo role of tonic Rasgrp1-mTORC1 in T cells as well as the metabolic and immunological implications of this signal and self-recognition for naïve T cells (Aim 2). Lastly, we will characterize the tonic signals and metabolic state of self-reactive CD4+ T cells from SLE and RA patient samples with single cell resolution (Aim 3). The synergistic aims and secured new cell lines, new mouse models, new patient sample pipelines, and innovative, single cell-resolution technology platforms will allow us to make significant contributions towards increased mechanistic understanding of self-recognition, tonic signaling, and spurious activation and differentiation of pathogenic CD4+ T cell subsets in autoimmune diseases.

项目总结/摘要 自身反应性CD 4 + T细胞在自身免疫性疾病的发展中起重要作用， 系统性红斑狼疮（SLE），并经常纠缠在一个刺激环与其他免疫细胞。 引起组织损伤和自身抗原释放的自身抗体导致进一步的假激活 和自身反应性CD 4 + T细胞的分化。目前还不清楚是通过什么分子机制 异常的自我识别可导致T细胞内在控制的丧失。巡逻的T细胞不断遇到 自我肽（自我p/MHC）和自我识别驱动低水平的紧张信号。自20世纪80年代末以来， 信号已经在静止的T细胞中被检测到，但这些信号的功能长期以来一直是个谜。 在1 R 01 AI 104789期间，我们发现紧张性信号动态控制幼稚CD 4 + T细胞 状态紧张性信号通过免疫抑制剂抑制幼稚T细胞的假激活和分化。 转录诱导的靶基因的功能作为刹车。另一方面，我们也透露， 强直信号通过翻译其他靶基因来启动幼稚T细胞的细胞活性，从而提高T细胞的免疫功能。 能量和代谢状态。第二种类型的主音信号是通过一种新发现的 T-Rasgrp 1-mTORC 1通路，并导致大约3000个基因的组成性mRNA翻译。 静息CD 4 + T细胞。紧张性mTORC 1信号具有令人惊讶的选择性和鲁棒性， 通过Rasgrp 1中的自我识别和SNV（单核苷酸变体）升高。带有Rasgrp 1Anaef的T细胞 变异显示增加张力mTORC 1信号，异常翻译mRNA靶，自发 在ICOS+PD-1+ CXCR 5-Bcl 6- T外周辅助（TPH）细胞中分化，并导致 B细胞自身抗体。这些研究提供了一个框架，以获得分子或机制 了解自我识别，紧张信号，T细胞生物学和自身免疫。 我们的更新重点是了解异常的自我识别和增强的强直Rasgrp 1- 随着时间的推移，mTORC 1信号可以导致幼稚CD 4 + T细胞的代谢改变，并最终驱动 致病性CD 4 + T细胞亚群的假活化和分化。我们将调查新的非- 我们发现的经典的、紧张的Rasgrp 1-mTORC 1信号通路（Aim 1）。我们将建立在 T-Rasgrp 1-mTORC 1在T细胞中的体内作用以及T-Rasgrp 1-mTORC 1的代谢和免疫学意义 这种信号和幼稚T细胞的自我识别（Aim 2）。最后，我们将描述主音信号的特征， 来自SLE和RA患者样本的自身反应性CD 4 + T细胞的代谢状态与单细胞分辨率 (Aim（3）第三章。协同目标和安全的新细胞系，新的小鼠模型，新的患者样本管道， 创新的单细胞分辨率技术平台将使我们能够做出重大贡献， 增加对自我识别、紧张性信号和虚假激活的机械理解 以及自身免疫性疾病中致病性CD 4 + T细胞亚群的分化。