# Muscle Tregs in health and disease

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2022 · $368,808

## Abstract

Beyond its primary function of repelling microbial challenges, the immune system plays important roles
in safeguarding tissue homeostasis. Macrophages have long been recognized to exercise such secondary
functions and, over the past several years, there has been growing interest in the implication of Foxp3+CD4+
regulatory T cells (or Tregs) in homeostatic processes. For example, unique Treg compartments in a number
of parenchymal tissues promote local repair/regeneration after acute or chronic injury – even in zebrafish!
 Skeletal-muscle Tregs serve as a paradigmatic pro-regenerative regulatory T cell population. First
reported by our lab in 2012, muscle Tregs increase rapidly after acute injury, differing from lymphoid-organ
Tregs in their elevated representation, tissue-adapted transcriptome, distinct – clonally expanded – T cell
receptor repertoire, and growth/survival factor dependencies. One intriguing axis, discovered during the last
funding-cycle, entails nociceptive neuron production of the peptide, CGRP; which elicits IL-33 production from
stromal cells; which, in turn, promotes local Treg accumulation. Muscle Tregs exert multiple influences along
the course of tissue repair – on both lymphoid and non-lymphoid cells during both the early, pro-inflammatory,
and late, pro-regenerative, phases. This broad range of activities highlights the need to go beyond the current
static image of muscle-Treg phenotype and function to obtain a dynamic view spanning the entire process.
 Temporal single-cell RNAseq data on the muscle-Treg compartment from 1-14 days post-injury
(generated during the last funding-cycle) revealed five distinct subtypes that waxed and waned over time:
circulating, recently activated, RORγ+, T-bet+ and GATA3+ (or reparative). Our long-term goal is to
understand how the five muscle-Treg subtypes integrate with each other and with neighboring
lymphoid and non-lymphoid cells to promote muscle regeneration. Our overall hypothesis is that
individual subtypes emerge and/or expand to deal with particular biological issues that arise during
the repair/regeneration process. In particular, this proposed project aims to:
1. Identify the provenance of RORγ+ skeletal-muscle Tregs.
2. Determine what critical role(s) RORγ+ Tregs play in effective muscle repair/regeneration.
3. Determine whether endogenous CGRP orchestrates increased IL-33 production by muscle MSCs and
consequent expansion of the reparative (GATA3+) muscle-Treg subtype.
 Completion of these studies will provide us with a more accurate and nuanced picture of Treg activities
during muscle regeneration. Potential therapeutic applications are many: catastrophic wound healing, exercise-
induced damage, age-related sarcopenias, muscular dystrophies, autoimmune myositides and chronic muscle
infections.

## Key facts

- **NIH application ID:** 10333370
- **Project number:** 5R01AR070334-07
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** DIANE J MATHIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $368,808
- **Award type:** 5
- **Project period:** 2016-05-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10333370

## Citation

> US National Institutes of Health, RePORTER application 10333370, Muscle Tregs in health and disease (5R01AR070334-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10333370. Licensed CC0.

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