# Orchestrating intestinal immunity through microbiota-CX3CR1+ cell interactions

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $393,910

## Abstract

Project Summary
The development and responsiveness of the mammalian immune system is shaped by a dynamic interaction
between the host immune system and the resident microbiota. The development of a host of human diseases
is associated with shifts in the microbiota alongside alterations in the intestinal immune responses. We
previously established that a population of mononuclear phagocytes (MNPs) expressing the CX3CR1
chemokine receptor play a central role in the immune system's responses to the microbiota and regulation of
intestinal homeostasis. In the presence of the microbiota, CX3CR1+ MNPs limit inflammatory immune
responses against both pathogenic bacterial infections and the microbiota itself in addition to promoting Treg
responses against soluble fed proteins. In contrast, removal of the microbiota promotes inflammatory T cell
responses brought about by dysregulation in a number of CX3CR1+ MNP functions, including production of the
anti-inflammatory cytokine IL-10 and clearance of intracellular bacteria. Further dysregulation of CX3CR1+ MNP
function is associated with pathology in inflammatory conditions such as inflammatory bowel disease (IBD). We
therefore hypothesize that under normal conditions, specific members of the microbiota activate cellular
pathways in CX3CR1+ MNPs responsible for limiting intestinal inflammation by restraining inflammatory T cell
responses and promoting intestinal mucosal barrier function. Conversely, the shifted microbiota composition
frequently associated with gastrointestinal infection or inflammatory disorders such as IBD provide alternative
signals to CX3CR1+ MNPs, driving them to pathogen clearance and promoting intestinal inflammation.
Reestablishing the normal microbiota should then direct CX3CR1+ MNPs to restore intestinal homeostasis. To
address the in vivo role for CX3CR1+ MNPs in the induction of intestinal immune responses, we generated
novel mouse strains in which CX3CR1+ MNPs can be selectively depleted. We will use these mice in
conjunction with ex vivo assays to study the regulation of homeostatic functions in CX3CR1+ MNPs by the
microbiota as a whole as well as by select individual members. In Aim 1, we will determine how the microbiota
modulates CX3CR1+ MNP function to promote regulatory T cell responses and limit inflammation. In Aim 2, we
will determine the impact of individual members of the microbiota and their gene products on CX3CR1+ MNP-
induced anti-inflammatory T cell responses. At the conclusion of these studies, we will have identified and
characterized cellular pathways regulated by the microbiota that are designed to limit inflammation as well as
the microbial gene products responsible for the induction of these anti-inflammatory pathways. Together, these
studies will provide critical insights into the modulation of anti-inflammatory responses in the intestine by the
microbiota and will facilitate the identification of additional clinical targets for promoting and reestablishing...

## Key facts

- **NIH application ID:** 9876970
- **Project number:** 5R01AI125264-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** GRETCHEN E DIEHL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $393,910
- **Award type:** 5
- **Project period:** 2017-03-02 → 2020-09-11

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9876970

## Citation

> US National Institutes of Health, RePORTER application 9876970, Orchestrating intestinal immunity through microbiota-CX3CR1+ cell interactions (5R01AI125264-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9876970. Licensed CC0.

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