# Investigating the tissue location and protective function of oral vaccine-specific tissue resident memory CD4 T cells

> **NIH NIH R03** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $74,842

## Abstract

Abstract
Vaccination is our most important preventative therapy against infectious disease. Protective immunity at
mucosal sites has the potential to prevent re-infection by stopping invasion of the host. The small intestinal
mucosa is amongst the most common sites of infection, but the mechanisms of vaccine-induced immune-
mediated protection at this site remain relatively unknown. The primary target of an effective vaccine is the
creation of long-lived B cells and T cells that provide durable protection. How CD4+ T cells might contribute to
vaccine-mediated protection is unclear. We have developed a model of oral vaccination with an attenuated
version of the E. coli heat labile toxin (LT) that induces large populations of vaccine-specific CD4+ T cells that
are necessary for protection against re-infection. Using MHC class II tetramers we demonstrated that oral
vaccination induces a long-lived population of LT-specific intestinal memory CD4+ T cells share a
transcriptomic signature with Tissue-resident memory T cells (Trms). LT-specific T cells also expressed genes
associated with enteric nerve function and after vaccination CD4+ T cells were observed adjacent to enteric
nerves. Our hypothesis is that oral vaccine-specific CD4+ Trms protect the intestine by interacting with nerves
to activate motility and physically expel enteric pathogens upon re-encountering their antigen. To test this
question we need to develop a novel T cell receptor (TCR) transgenic mouse, specific to a dominant MHC
class II-restricted antigen from LT. Via adoptive transfer of LT-specific TCR transgenic memory T cells we can
test the hypothesis that these cells are sufficient to mediate protection against enteric infection. Further, LT-
specific TCR transgenic T cells can be easily identified in tissues using congenic markers and we propose to
use them to identify which nerves oral vaccine-activated CD4+ T cells interact with in the small intestine. At the
conclusion of this grant we will have developed a first in its kind TCR transgenic mouse that will drastically
increase our ability to make important discoveries about the biology and protective effects of CD4+ Trms in the
small intestine, but also will undoubtedly be of use to the scientific community interested in oral vaccines.

## Key facts

- **NIH application ID:** 10771288
- **Project number:** 5R03AI176019-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Timothy Wesley Hand
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $74,842
- **Award type:** 5
- **Project period:** 2023-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10771288

## Citation

> US National Institutes of Health, RePORTER application 10771288, Investigating the tissue location and protective function of oral vaccine-specific tissue resident memory CD4 T cells (5R03AI176019-02). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10771288. Licensed CC0.

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