# T cell Tolerance to Enteric Commensal Bacteria

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $502,369

## Abstract

PROJECT SUMMARY
 The gastrointestinal tract is colonized by an enormous collection of commensal bacteria living in
harmony with the host. This poses a challenge for the immune system which must promote tolerance to
beneficial bacteria species while still providing protection against pathogenic species. Indeed, a breakdown in
such discrimination is thought to be a major underlying cause of inflammatory bowel disease (IBD).
 Unlike self-antigens, antigens derived from commensal microbiota are unlikely to be presented in the
thymus to impact central T cell tolerance. Rather, specific tolerance to these antigens must rely exclusively on
peripheral mechanisms acting within the immune environment of the gut. However, these mechanisms and
the quality of the tolerance they mediate are unclear. To better investigate these processes, our lab has
developed peptide:MHCII tetramer reagents that enable us to directly identify rare gut CD4+ T cells with
specificity to immunodominant epitopes from several different commensal bacteria species in mice. Our
preliminary studies support varied roles for deletion, Treg, and Tr1 cell development depending on the bacteria
species. To provide better resolution of commensal antigen-specific T cell phenotypes as well as the
heterogeneity of these phenotypes within the overall antigen-specific population, we are combining our use of
tetramers with single cell RNA-seq transcriptomics to comprehensively define phenotypic and clonal
heterogeneity within distinct commensal antigen-specific CD4+ T cell populations.
 The overarching goal of this project is to understand the mechanisms by which T cells maintain immune
tolerance to specific commensal bacteria of the gastrointestinal tract so that they may ultimately be
manipulated for therapeutic benefit. We hypothesize that tolerance to commensal bacterial antigens is
maintained by multiple CD4+ T cell fates, each making unique but overlapping functional contributions that
collectively establish durable tolerance in the face of the dynamic gut environment. We will test this hypothesis
by 1) defining developmental fates for commensal bacterial antigen-specific CD4+ T cells that contribute to
immune tolerance, and 2) characterizing the function of commensal antigen-specific regulatory T cell subsets.

## Key facts

- **NIH application ID:** 10424555
- **Project number:** 5R01DK126910-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** James J Moon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $502,369
- **Award type:** 5
- **Project period:** 2021-06-09 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10424555

## Citation

> US National Institutes of Health, RePORTER application 10424555, T cell Tolerance to Enteric Commensal Bacteria (5R01DK126910-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10424555. Licensed CC0.

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