# Impact of priming on the generation of intestinal tissue-resident memory T cells

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2024 · $509,127

## Abstract

PROJECT SUMMARY/ABSTRACT
 There is a critical gap in our knowledge of the mechanisms during CD8 T cell priming that promote
tissue-resident memory CD8 T (TRM) cell development. In the absence of such knowledge, the realization of
developing vaccination strategies that elicit robust memory T cells at sites of pathogen invasion or tumor
development remain unlikely. The long-term goal is to determine the mechanisms that regulate the induction
and maintenance of TRM cells to improve vaccine efficacy. The overall objective in this application is to define
how priming influences the in situ development of intestinal CD8 TRM cells. The central hypothesis is that direct
retinoic acid signals during T cell priming in the gut draining lymph nodes license CD8 TRM cell development in
the intestine. This hypothesis is based on rigorous preliminary data that suggests that retinoic acid licenses
CD8 TRM precursor cell development independent of the well known CCR9-mediated gut migration pathway.
The rationale that underlies the proposed research is that knowledge of the factors that promote CD8 TRM cell
development will provide a strong scientific framework to develop more effective and targeted vaccination
strategies. The central hypothesis will be tested by pursuing three specific aims: 1) To test the hypothesis that
priming in mesenteric lymph nodes promotes intestinal CD103+ CD8 TRM cell differentiation; 2) To test the
hypothesis that retinoic acid licenses intestinal CD103+ CD8 TRM cell development; and 3) To test the
hypothesis that dietary vitamin A enhances CD103+ CD8 TRM cell development to improve vaccine efficacy.
MLN or spleen derived cells will be used to assess CD103+ CD8 TRM cell development in the gut and in distal
tissues after foodborne infection. Agonists and antagonists of retinoic acid receptors (RAR) in combination with
RAR and CCR9 knockout mouse models will be used to determine how retinoic acid licenses intestinal CD8
TRM cell development. Finally, vitamin A deficient or supplemented diets will be used to modulate retinoic acid
and assess vaccine immunogenicity and efficacy. The proposed research is innovative because it utilizes
foodborne infection with a mouse adapted human pathogen, Listeria monocytogenes, to interrogate intestinal T
cell responses. The proposed research is significant because it is expected to define novel pathways through
which retinoic acid impacts intestinal CD8 TRM cell development independent of CCR9 and gut migration.
Ultimately, such knowledge can be applied to improve rationale vaccine design targeting gastrointestinal
pathogens or immunization in malnourished individuals with vitamin A deficiency.

## Key facts

- **NIH application ID:** 10886637
- **Project number:** 5R01AI172919-03
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Brian S Sheridan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $509,127
- **Award type:** 5
- **Project period:** 2022-09-19 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10886637

## Citation

> US National Institutes of Health, RePORTER application 10886637, Impact of priming on the generation of intestinal tissue-resident memory T cells (5R01AI172919-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10886637. Licensed CC0.

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