# Determinants of induced Treg and inflammatory Th17 cell balance in response to potentially pathogenic microbiota

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $521,077

## Abstract

Interactions of the gut microbiota with cells of the immune system govern multiple physiological functions that
are manifested locally, in the regulation of intestinal barrier functions, and systemically, in autoimmune
diseases and modulation of anti-tumor immunity. Although mutualistic microbial species generally provide vital
health benefits to the host, some of them can conditionally cause harm under some circumstances, such as
host genetic vulnerabilities or following environmental perturbation. These bacterial species, known as
“pathobionts”, have been proposed to be major contributors to inflammatory bowel diseases (IBD) such as
ulcerative colitis and Crohn’s disease, which are characterized by intestinal dysbiosis. A better characterization
of these bacterial species and the mechanisms by which they interact with the host in healthy homeostatic
conditions and during IBD-associated inflammation is critical for developing better therapeutic approaches. We
study the model pathobiont Helicobacter hepaticus, which induces regulatory T cells (iTreg) in the healthy
murine gut, but promotes Th17-mediated inflammation when the iTregs are compromised. H. hepaticus-
specific naïve T cells are activated by antigen-presenting cells (APCs) in colon-draining mesenteric lymph
nodes (mLN), and up-regulate Foxp3 and RORgt, transcription factors characteristic of intestinal iTreg.
However, when IL-10 is limiting or when iTreg induction is otherwise compromised, the microbe-specific T cells
express RORgt and adopt a pathogenic (p)Th17 cell program in the lamina propria. The goals of this proposal
are to identify the APCs that interact with naïve H. hepaticus-specific T cells in the mLN to program either iTreg
or pTh17 differentiation pathways, elucidate the molecules involved and the temporal dynamics of the APC-T
cell interactions, and determine the roles of the diverse types of MHC class II-expressing cells in the intestinal
lamina propria in promoting iTreg and pTh17 cell functions. In preliminary studies, we found that selective loss
of either CCR7 in dendritic cells (DCs) or MHC-II in type 3 innate lymphoid cells (ILC3) resulted in abrogation
of iTreg cell differentiation and in expansion, instead, of pTh17 cells in mLN and lamina propria. A similar iTreg
phenotype was observed when molecules involved in TGF-b release were mutated in DCs or ILC3, suggesting
that regulated local release of this iTreg-inducing cytokine requires naïve T cells to interact with both DCs and
ILC3. Our first aim is to precisely characterize, through genetic and transcriptomic approaches, the cell types
required for iTreg induction in the mLN, and rule out potential for misinterpretation due to expression of Cre in
rare uncharacterized APCs or to indirect effects of the cell type-restricted mutations; and determine the
spatiotemporal interactions of the cells, using multiphoton microscopy. The second aim is to identify the CCR7-
independent APC(s) required for pTh17 cell inducti...

## Key facts

- **NIH application ID:** 10185533
- **Project number:** 1R01AI158687-01
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Dan Littman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $521,077
- **Award type:** 1
- **Project period:** 2021-03-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10185533

## Citation

> US National Institutes of Health, RePORTER application 10185533, Determinants of induced Treg and inflammatory Th17 cell balance in response to potentially pathogenic microbiota (1R01AI158687-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10185533. Licensed CC0.

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