Understand the metabolic fitness of naïve T cells

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。 引起组织损伤和自身抗原释放的自身抗体会导致进一步的假性激活和 自身反应性CD4+T细胞的分化。目前尚不清楚是什么分子机制导致了自闭症 识别可能会导致T细胞失去内在控制。在健康的动态平衡条件下，巡逻的T细胞 遇到自体多肽(self-p)和自身p/MHC的相互作用会在T细胞中驱动低水平的紧张性信号 在自身免疫的背景下，已经讨论了紧张性信号。在这里我们将调查一下补药是如何 T细胞中的信号与T细胞新陈代谢有关。 我们过去的努力产生了一种全新的分子范式，即T细胞受体如何自我识别 (TCR)和由此产生的紧张性信号动态调节静止的CD4+T细胞的幼稚状态。《玫瑰》 实验室发现了一条新的RASGRP1-mTORC1通路，可能是由Self-p/MHC-TCR信号触发的。这个 紧张性RASGRP1-mTOR信号在幼稚T细胞中的作用及其在自体肽/MHC-TCR下游的活性 信号，它对紧张性T细胞新陈代谢的影响，以及这些过程与 自身免疫性疾病是完全未知的。我们在此发现并呈现的T细胞免疫学 该提议提供了一个框架，并可能在mTOR信号、细胞新陈代谢和 T细胞的自身反应性。我们和优化的条形码、磷流、光谱流和SCENITH- 技术我们处于有利的地位，可以帮助候选人取得重大进展，了解 T细胞自我识别的机制含义以及自我识别(自动反应)的增加如何导致 改变T细胞的新陈代谢。 这里提出的多样性补充研究属于家长P01补助金的范围和 与父P01中的项目4最一致。我们将机械地将自我认知与mTORC1联系起来 信号，研究紧张性mTOR信号和自身p/MHC相互作用对T细胞代谢的影响，以及 通过询问mTOR靶mRNAs来研究初始T细胞的核糖体活性。我们设计了一种 为候选人制定详细的职业规划，以推动她的职业生涯向前发展。Roose博士有很好的指导 资历和优秀导师的良好履历。

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. Under healthy homeostatic conditions, patrolling T cells encounter self-peptides (self-p) and self-p/MHC interactions drive low-level, tonic signals in T cells and these tonic signals have been discussed in the context of autoimmunity. Here we will investigate whether how tonic signals in T cells connect to T cell metabolism. Our past efforts generated an entirely new molecular paradigm how self-recognition by the T cell receptor (TCR) and the resultant tonic signals dynamically regulate the naïve state of resting CD4+ T cells. The Roose lab discovered a novel RasGRP1-mTORC1 pathway that is likely triggered by self-p/MHC-TCR signals. The function of tonic Rasgrp1-mTOR signals in naïve T cells, its activity downstream of self-peptide/MHC-TCR signals, its effects on tonic T cell metabolism, and the connections and relevance of these processes to autoimmune diseases are completely unknown. The T cell immunology we discovered and present in this proposal provides a framework and possible mechanistic link between mTOR signals, cell metabolism, and autoreactivity of T cells. We and optimized, barcoding-, phospho-flow-, spectral flow-, and SCENITH- technology. We are in an excellent position to aid the candidate to make significant progress to understand the mechanistic implication of self-recognition by T cells and how increased self-recognition (auto-reactivity) leads to altered metabolism of T cells. The proposed research for the Diversity Supplement here is within the scope of the parent P01 grant and most aligned with Project 4 in the parent P01. We will mechanistically connect self-recognition to mTORC1 signals, investigate the impact of tonic mTOR signals and self-p/MHC interactions on T cell metabolism, and study the ribosome activity of naïve T cells by interrogating mTOR target mRNAs. We have designed a detailed career plan for the candidate to propel her career forward. Dr. Roose has excellent mentoring credentials and a proven track record of outstanding mentoring.