# Dissecting the intestinal niche for regulatory T cells

> **NIH VA I01** · PHILADELPHIA VA MEDICAL CENTER · 2024 · —

## Abstract

1. Objective: Inflammatory bowel diseases (IBD), including Crohns Disease and Ulcerative Colitis, arise in
genetically-susceptible hosts when intestinal epithelial defects and heightened responsiveness towards
commensal organisms lead to excessive activation of CD4+ T cells and tissue damage. IBD is also associated
with loss of regulatory pathways including defects in regulatory T cells (Tregs). Tregs, a subset of Foxp3-
positive CD4+ T cells, are central to intestinal tolerance; they prevent the development of IBD disease and
suppress inflammation during infection. In this application, we seek to understand the mechanisms that
maintain intestinal Tregs during health and inflammation. Regulatory T cells include two developmentally
distinct subsets: thymus-derived (tTreg or natural (nTreg) and peripherally-derived (pTreg) that differentiate
from conventional naïve CD4+ T cells. Human and mouse intestine contain cells of both lineages and both are
necessary to maintain tolerance. Foxp3-deficient IPEX patients, lacking natural Tregs, develop autoimmune
enteritis as infants. Separately, loss of the genomic region that controls peripheral differentiation of pTregs also
leads to intestinal inflammation. Thus, both murine and human studies demonstrate a requirement for both
populations for the maintenance of intestinal tolerance. There are no data defining distinct mechanistic or
anatomic requirements for the two populations.
 Treg localization and phenotypes were examined in mice lacking peripheral TCR-MHCII interactions
and peripheral conversion of Tregs (pTregs). Thymically-generated nTregs entered the small intestine lamina
propria (siLP) to fill the compartment in the absence of MHCII. Imaging of intact tissue shows that Tregs in the
siLP have two distinct anatomic locations: individually localized within the siLP villus or clustered within
organized structures resembling isolated lymphoid follicles (ILFs). Our data suggest that a subset of Tregs
preferentially localize to ILFs; this association is altered during infection. Additionally, nTregs and pTregs
occupy an overlapping niche despite having different requirements for costimulatory signals. Thus, we present
the hypotheses that 1. thymic-derived and peripheral Tregs occupy distinct physiologic niches in the
small intestine, and 2 ILFs provide a niche for Tregs that is malleable during inflammation.
2. Research Design: In our first Aim, we will utilize murine models and healthy human tissue to determine if
ILFs are required for the maintenance of siLP Tregs, define the costimulatory signals present in the ILF, and
then ask if the ILF specifically attracts and maintains thymic Tregs in contrast to pTregs. Multiple studies in
mice and men find that both infectious and autoimmune intestinal inflammation is associated with expansion of
ILFs and altered Treg dynamics. Yet, there are no data on how these changes affect the positioning and
maintenance of Tregs and recovery from inflammation. In our se...

## Key facts

- **NIH application ID:** 10765657
- **Project number:** 5I01BX005685-02
- **Recipient organization:** PHILADELPHIA VA MEDICAL CENTER
- **Principal Investigator:** TERRI M. LAUFER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-12-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765657

## Citation

> US National Institutes of Health, RePORTER application 10765657, Dissecting the intestinal niche for regulatory T cells (5I01BX005685-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10765657. Licensed CC0.

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