# A mechanism to minimize auto-reactivity in the tissue-resident memory T cell pool

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $478,063

## Abstract

Project Summary
Thymic T cell development produces peripheral T cell receptor repertoires with significant residual reactivity
against our self-antigens. Several mechanisms have emerged to manage this self-reactivity and prevent overt
auto-immunity, including T cell anergy and deletion, as well as the activities of regulatory T cells. Failure of
such tolerance mechanisms is thought to underlie many autoimmune disease.
In studying the naive CD8+ T cell pool in mice, we have recently observed that a fraction of naive T cells are –
under homeostatic conditions – exposed to active TGF-b during MHC-I-dependent interactions with migratory
dendritic cells in lymph nodes. This TGF-b exposure pre-conditions naive CD8+ T cells to efficiently form
epithelial-resident memory T cells (eTRM) upon immune challenges, such as skin vaccination against viral
pathogens. When this pre-conditioning process is disrupted, e.g. in the absence of lymph nodes, by preventing
dendritic cell migration to lymph nodes, or by deleting TGF-b-activating aV-integrins in dendritic cells, formation
of eTRM in skin is strongly reduced, causing diminished antiviral protection.
In preliminary studies for this project we have discovered that homeostatic TGF-b conditioning occurs
preferentially in weakly self-reactive CD8+ T cells, while more strongly self-reactive cells are not conditioned.
Mechanistically, TCR-dependent ERK activity appears to restrict TGF-b signaling through an inhibitory
phosphorylation of the linker region in Smad2 and Smad3 transcription factors that prevents their nuclear
translocation and effects on gene transcription.
Based on these observations we hypothesize that homeostatic TGF-b signals that condition naive CD8+ T cells
for the formation of long-lived epithelial resident memory cells are restricted to cells that pose the lowest risk of
causing autoimmunity. In this project we will test this hypothesis by comparing TCR self-reactivity in naive
CD8+ T cells as well as the eTRM pools in skin and other barrier tissues, and by examining epigenetic changes
that characterize conditioned naive T cells and their relation to gene programs activated during eTRM
differentiation. If our hypothesis is confirmed, our studies could reveal a new mechanism by which auto-
reactivity in the peripheral TCR repertoire is managed. Breakdown of this mechanism could underlie
autoimmune diseases that manifest in barrier tissues such as the skin.

## Key facts

- **NIH application ID:** 10280282
- **Project number:** 1R01AI163223-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Thorsten Roman Mempel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $478,063
- **Award type:** 1
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10280282

## Citation

> US National Institutes of Health, RePORTER application 10280282, A mechanism to minimize auto-reactivity in the tissue-resident memory T cell pool (1R01AI163223-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10280282. Licensed CC0.

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