Understand the metabolic fitness of naïve T cells

项目总结/文摘

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.