# Local immune tolerance in the large intestine mediated by GPR15

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $546,983

## Abstract

PROJECT SUMMARY/ABSTRACT
It is critical that the host immune system does not mount outright inflammatory responses against foreign
antigens abundant in the lumen of the intestine (such as dietary antigens exposed through the small intestine
mucosa and microbial antigens coming predominantly from the lumen of the large intestine). Failure in this
process leads to a significant health threat to the host as evidenced by prevalence of celiac disease and
inflammatory bowel diseases. Regulatory T cells (Tregs) have evolved to play a critical role to ensure this
tolerance. Dietary antigens are known to generate inducible Tregs (iTregs) and systemic tolerance against
those antigens is achieved by circulation of these iTregs throughout the body (oral tolerance). In contrast, it
may not be beneficial for the host to establish systemic, Treg-mediated tolerance against antigens from the
large intestine since self-replicating microbes, the primary source of antigens in the large intestine, can easily
escape and invade tissues outside of the intestine. Our long-term goal is to characterize how Treg-mediated
tolerance against antigens from the large intestine is accomplished. Our central hypotheses are that activation
of the aryl hydrocarbon receptor (AHR) in T cells induces GPR15 expression and promotes iTreg differentiation
simultaneously to produce GPR15+ iTregs and that the GPR15-C10orf99 receptor-ligand pair mediates the
retention of Tregs in the large intestine and prevents systemic dissemination of iTregs, accomplishing local
tolerance by GPR15+ iTregs. Guided by strong preliminary data, we have generated novel mouse models that
will enable us to test these hypotheses. We propose to pursue the following two aims: (1) To characterize
Treg-mediated immune tolerance against microbial antigens in the large intestine compared to systemic oral
tolerance against dietary antigens from the small intestine, we will check whether GPR15-C10orf99 mediate
trafficking of Tregs inside the large intestine lamina propria and Treg retention, in addition to their known
function during extravasation. We will also determine the fate of GPR15+ iTregs and the consequences in
Treg-mediated tolerance against gut microbial antigens after inducible deletion of GPR15. (2) To characterize
the effect of AHR signaling on iTreg differentiation and GPR15 induction, we will test chemicals with reported
AHR ligand activity for their ability to induce FOXP3 and GPR15 expression. We will also examine
mechanisms underlying AHR-induced increase of GPR15+ Tregs in vivo at the cellular level. To understand the
molecular mechanisms for AHR-mediated expression of FOXP3 and GPR15, we will perform CHIPseq
analysis in T cells after AHR activation by specific ligands that we will identify. Our findings will significantly
advance understanding of Treg-mediated tolerance and will help to develop novel therapeutic strategies to
treat various immunological disorders.

## Key facts

- **NIH application ID:** 9971874
- **Project number:** 1R01AI141787-01A1
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Sangwon Vincent Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $546,983
- **Award type:** 1
- **Project period:** 2020-02-21 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971874

## Citation

> US National Institutes of Health, RePORTER application 9971874, Local immune tolerance in the large intestine mediated by GPR15 (1R01AI141787-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9971874. Licensed CC0.

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