# Understand the metabolic fitness of naïve T cells

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $64,393

## Abstract

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.

## Key facts

- **NIH application ID:** 10798720
- **Project number:** 3P01AI091580-12S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** JEROEN ROOSE
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $64,393
- **Award type:** 3
- **Project period:** 2011-07-15 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10798720

## Citation

> US National Institutes of Health, RePORTER application 10798720, Understand the metabolic fitness of naïve T cells (3P01AI091580-12S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10798720. Licensed CC0.

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