# Intestinal CD4 T cell responses to dietary and microbial antigens

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2022 · $615,247

## Abstract

Project Summary
The highly specialized intestinal immune system is charged with maintaining tolerance to harmless stimuli from
commensal bacteria and food, while providing protective immunity against pathogens. Dysregulation of this
critical balance can lead to inflammatory bowel disease, food allergy, or increased susceptibility to enteric
pathogens. CD4+ T cells are key players in intestinal homeostasis, finely tuning responses at the level of antigen
recognition and functional differentiation. In the intestinal epithelium (IE) and underlying lamina propria (LP),
tissue adapted pro-inflammatory (ie. Th17, Th1) and regulatory (Treg) and intraepithelial (CD8aa+ CD4IEL) CD4+
T cells coordinate immunity and tolerance to diverse intestinal stimuli. Nevertheless, it remains to be defined
how TCR repertoire and its specificity translate to function of both LP and IELs in response to microbial antigens.
Additionally, very little is known about the characteristics of dietary antigen-specific intestinal T cells. Oral
tolerance, a critical mechanism of gut homeostasis whereby oral administration of antigen results in both local
and systemic tolerance to that antigen, is known to depend on Tregs. However, the clonal dynamics of polyclonal
T cell responses in the setting of tolerance remain unclear. Finally, outside the context of immunization or allergy,
T cells that specifically recognize food protein have yet to be identified. Based on data recently published as well
as preliminary data obtained during the current funding cycle, we hypothesize that tissue cues combined with
TCR-driven signals from commensal microbes and food dictate intestinal T cell functional differentiation in steady
state, while disruption of normal T cell responses by infections or allergens results in inappropriate clonal
dynamics including expansion of pathological T cells. Aim 1 will define how stimulation by microbiota or enteric
viruses impact TCR repertoire and functional differentiation of intestinal CD4 T cells. Aim 2 will characterize the
role of dietary antigens in the context of tolerance, enteric infections, or food allergy, affect TCR repertoire and
functional differentiation of intestinal CD4 T cells. We combine single cell transcriptomics with a novel fate-
mapping strategy to selectively label peripheral T cells that are recruited to the intestine under various microbial
and dietary challenges. A recently developed LIPSTIC tool that allows intestinal epithelial cells (IECs) labeling
of interacting cells will be utilized to define potential mechanisms of IEL recruitment/expansion in response to
nonself stimuli. Recently generated murine strains with fixed TCR Vb chain, or that carry microbiota-specific
TCRs, combined with complementary tetramer and gnotobiotic strategies will be used to specifically track and
define recognition properties during T cell migration and differentiation in the gut. Novel “super-tetramer” and
dietary manipulations, combined with inflammator...

## Key facts

- **NIH application ID:** 10390787
- **Project number:** 2R01DK093674-10
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Daniel S Mucida
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $615,247
- **Award type:** 2
- **Project period:** 2013-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10390787

## Citation

> US National Institutes of Health, RePORTER application 10390787, Intestinal CD4 T cell responses to dietary and microbial antigens (2R01DK093674-10). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10390787. Licensed CC0.

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