# Regulation of T cell responses to oral antigens

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $402,500

## Abstract

Immune responses triggered by oral antigens can have significant clinical consequences. Dendritic cells (DCs)
are among the most important cellular determinants of oral tolerance, as they are tasked, in a mucosal
environment that also contains antigens and pattern stimuli derived from vast commensal microbiota, with
deciding whether adaptive immunity should be mobilized or tolerized to given antigens. We have recently
generated a DC-specific mouse model of spontaneous Th2-associated disease of the small intestine (SI)
called TRAF6ΔDC, which initially appeared to be microbiota-dependent because antibiotic treatment is
ameliorative. However, germ-free (GF) TRAF6ΔDC mice surprisingly exhibit exacerbated disease compared to
mice housed under specific pathogen-free (SPF) conditions, suggesting a trigger other than microbiota. We
now have preliminary findings that TRAF6ΔDC disease is completely ameliorated in mice fed antigen-free (AF)
diet, suggesting the driving stimulus of disease is food antigen. The TRAF6ΔDC model may be employed to
reveal novel mechanisms underpinning DC-mediated oral tolerance, and thus we propose the following
specific aims: 1. Investigate the immunological mechanisms of TRAF6ΔDC oral antigen sensitivity. We
propose to further characterize the immunologic abnormalities of TRAF6ΔDC mice in the context of oral
antigen sensitivity to elucidate novel immunologic mechanisms linking development and maintenance of oral
tolerance to TRAF6-mediated signals in DCs. In this respect, we will examine the relevant cellular actors, as
well as regulatory and effector molecules to determine how homeostasis is disrupted in the presence of oral
antigen. We will use diphtheria toxin receptor (DTR) transgenic mice to examine the effects of temporal
ablation of various types of DCs in the context of both DC-specific TRAF6 deficiency and oral tolerance
maintenance to begin to determine whether TRAF6 provides key pro-tolerance signals to certain cell types
versus creating dysfunctional DCs in its absence. Model oral antigen will also be utilized in TRAF6ΔDC mice to
better define the mechanism(s) of disease development. 2. Investigate the independent effects of microbiota
and antibiotics on TRAF6ΔDC oral antigen sensitivity. Mitigation of TRAF6ΔDC disease by antibiotics in the
absence of microbiota suggests potential biologically relevant direct effects of antibiotics on immune cells
which we propose to investigate in the context of TRAF6ΔDC oral antigen sensitivity in the presence or
absence of microbiota and/or food antigens. While we typically employ a broad-spectrum cocktail of four
antibiotic drugs from different classes for the purpose of microflora depletion, our hypothesis in these studies
will initially focus on the role of ampicillin, which belongs to the β-lactam class that has been previously
reported to have direct biotic immunomodulatory activity. Additionally, we will examine the effects of antibiotics
on oral antigen sensitivity in TRAF...

## Key facts

- **NIH application ID:** 9840865
- **Project number:** 5R01AI125284-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** YONGWON CHOI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2017-01-11 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840865

## Citation

> US National Institutes of Health, RePORTER application 9840865, Regulation of T cell responses to oral antigens (5R01AI125284-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840865. Licensed CC0.

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