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

项目摘要/摘要 自身反应性CD4+T细胞在自身免疫性疾病的发展中发挥重要作用，如 系统性红斑狼疮(SLE)，通常与其他免疫细胞纠缠在一个刺激环中。 导致组织损伤和自身抗原释放的自身抗体会导致进一步的虚假激活 和自我反应性CD4+T细胞的分化。目前尚不清楚是通过什么分子机制 异常的自我识别可能会导致T细胞失去内在控制。巡逻的T细胞经常遇到 自体多肽(self-p/MHC)和自我识别驱动低水平的紧张性信号。自20世纪80年代末以来，S，滋补 在静止的T细胞中检测到了信号，但这种信号的功能长期以来一直是个谜。 在1R01AI104789期间，我们发现紧张性信号动态控制幼稚的CD4+T细胞 州政府。强直信号通过抑制初始T细胞的假性激活和分化 作为刹车功能的目标基因的转录诱导。另一方面，我们也透露， 紧张素信号通过翻译其他靶基因来启动幼稚T细胞的细胞活性，这些靶基因可以提高 精力充沛的新陈代谢状态。这种第二种主音信号通过一种新发现的 强直的RASGRP1-mTORC1途径和导致大约3000个基因的结构性mRNA翻译 静息的CD4+T细胞。主音mTORC1信号令人惊讶地具有选择性和健壮性，并且异常 通过自我识别和RASGRP1中的SNV(单核苷酸变体)升高。带有Rasgrp1Anaef基因的T细胞 突变体显示增强的强直-mTORC1信号，自发地异常翻译mRNA靶标 在ICOS+PD-1+CXCR5-Bcl6-T外周辅助(TPH)细胞中分化，并导致致病产物 B细胞产生的自身抗体。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、紧张性信号、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认识和增强的紧张性RASGRP1- MTORC1信号可以导致幼稚的CD4+T细胞随着时间的推移而改变新陈代谢，最终驱动 致病的CD4+T细胞亚群的虚假激活和分化。我们将调查新的非 我们发现的规范的、紧张性的RASGRP1-mTORC1信号通路(目标1)。我们将建立智能网 紧张性RASGRP1-mTORC1在T细胞中的体内作用及其代谢和免疫学意义 这一信号和幼稚T细胞的自我识别(目标2)。最后，我们将描述主音信号和 单细胞分辨下SLE和RA患者自身反应性CD4+T细胞的代谢状态 (目标3)。协同的目标和确保了新的细胞系，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 提高对自我识别、强直信号和虚假激活的机械性理解 自身免疫性疾病致病的CD4+T细胞亚群的分化。

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.