# Mechanisms of reduced T cell autoimmunity with immune experience

> **NIH NIH R56** · UNIVERSITY OF MINNESOTA · 2022 · $408,685

## Abstract

The hygiene hypothesis states that there is an inverse correlation between exposure to microbes and the
development of autoimmunity, i.e., the “cleaner” your environment is, the higher probability autoimmunity will
develop. The reason for this is unclear. Thus, there are outstanding gaps in our knowledge about the hygiene
hypothesis, including what changes occur in the host after microbial exposure and how this affects self-specific
immunity leading to decreased autoimmunity. We have replicated aspects of the hygiene hypothesis using
tractable, antigen-specific mouse models of infection and autoimmunity. Our data show that previous induction
of T cell immunity under different conditioning contexts (infection or interaction with self-antigen) drives
decreased self-specific CD8 T cell activation months later. The presence of anergic OTI T cells decreases future
autoimmune pathology, as both the proliferation and function of self-specific CD8 T cells is blunted. We observe
the same outcome in LCMV immune mice and in `dirty' mice. Previous immune experience is linked to earlier
induction of a tolerant signature in responding self-specific CD8 T cells. This is specific for self-antigen, as
foreign-antigen-specific T cell responses are unaffected. These aims will test the hypothesis that previous T
cell responses alter self-antigen production and/or presentation in lymphoid tissue to speed tolerance induction.
Aim 1 will determine whether changes in stromal cells in lymph nodes contribute to decreased self-specific CD8
T cell activation in immune-experienced mice. OTI cell division in iFABP-ova mice is reduced 60h post priming
in inguinal LN of immune-experienced hosts, which is driven by non-migratory cells. As stromal cells in LN can
produce tissue-restricted antigens, changes in these cells may negatively affect self-specific CD8 T cell
activation. We will evaluate the number, epigenetic and phenotypic signature of LN stromal cells in naïve and
immune-experienced mice and test if type I IFN, IFN, IL-6 or TNF, are important for the observed changes.
Aim 2 will establish whether increased self-antigen presentation on LN stromal cells is responsible for decreased
autoimmunity. We will evaluate expression of tissue-restricted antigens in immune-experienced animals, as well
as factors important for their presentation, such as AIRE and DEAF1. Expression of these will be quantified in
conjunction with staining for Kb-SIINFEKL complexes, as well as in vivo imaging of T cells in live mice. Overall,
this application will determine the novel mechanisms by which self-antigen production or presentation is altered
due to previous environmental programming from the adaptive immune response. It also addresses the
important, but mechanistically unresolved, hygiene hypothesis, a fundamental topic intersecting TCR
responsiveness with environmental impact, leading to vastly different outcomes of tolerance or autoimmunity.

## Key facts

- **NIH application ID:** 10632556
- **Project number:** 1R56AI162742-01A1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** VAIVA D VEZYS
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $408,685
- **Award type:** 1
- **Project period:** 2022-06-14 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10632556

## Citation

> US National Institutes of Health, RePORTER application 10632556, Mechanisms of reduced T cell autoimmunity with immune experience (1R56AI162742-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10632556. Licensed CC0.

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