# Nutrient sensing and lysosomal signaling in regulatory T cells and immune tolerance

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2022 · $448,750

## Abstract

Program Description/Abstract
Regulatory T cells (Tregs) are central mediators of immune tolerance, but can also be a major hurdle to tumor
immunity and immunotherapy. Tregs respond to TCR stimulation in the periphery and develop into activated
Tregs (aTregs), whose function is important for tissue homeostasis in non-lymphoid organs and immune
regulation in the tumor microenvironment. In addition to TCRs, microenvironment-derived signals, especially
nutrients, have emerged as important regulators of T cell activation and differentiation, although the functional
importance of nutrients in Tregs and whether and how they signal are unclear. We have a long-standing interest
in understanding mTORC1 signaling in adaptive immunity and Treg biology. Our previous work has centered
upon understanding the immune functions of mTORC1. How upstream signals regulate mTORC1 to shape
Treg activation programs and tissue and tumor-specific responses remain poorly understood and will be the
focus of this renewal application. To this end, we performed an unbiased, genome-wide screen for regulators of
mTORC1 in Tregs, and identified the small G proteins RagA and Rheb1 among the top-ranking positive
regulators of mTORC1 activity. Treg-specific deletion of RagA led to mild TH1-associated autoimmune
responses, while loss of both RagA and the partially-redundant RagB resulted in the development of a fatal,
Scurfy-like inflammatory disorder. Mechanistically, we found that RagA/B linked amino acids to mTORC1
activation and the generation of aTregs. Furthermore, we identified the functional importance of Rheb1 and its
homolog Rheb2 in aTreg generation, and the interplay of RagA/B with Rheb and lysosomal signaling. We
hypothesize that amino acids signal via RagA/B and interplay with Rheb and lysosomal signaling to
license mTORC1 activation for functional programming of aTreg generation and suppressive activity.
Aim 1. Establish the effects and mechanisms of RagA/B signaling in aTreg generation and function. Aim 2.
Identify the integration of amino acid signals by TSC–Rheb and RagA/B in Tregs. Aim 3. Define lysosomal
signaling and reconstruct mTORC1 signaling circuits in Tregs. We predict our studies will establish a new
paradigm in Treg biology and mechanisms of mTORC1 regulation, with the potential to translate into innovative
strategies to target cancer and other diseases.

## Key facts

- **NIH application ID:** 10466817
- **Project number:** 5R01AI150514-09
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Hongbo Chi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $448,750
- **Award type:** 5
- **Project period:** 2014-09-19 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466817

## Citation

> US National Institutes of Health, RePORTER application 10466817, Nutrient sensing and lysosomal signaling in regulatory T cells and immune tolerance (5R01AI150514-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10466817. Licensed CC0.

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