# Autoreactive CD4 T cells in healthy mice

> **NIH NIH R01** · GEORGIA STATE UNIVERSITY · 2020 · $388,542

## Abstract

In the thymus, central tolerance should eliminate the majority of immature T cells that
express autoreactive, pathogenic antigen receptors (αβTCRs). However, an unknown number of
autoreactive cells escape deletion or commit to immunosuppressive, regulatory linage (Tregs).
Tregs control peripheral tolerance and sustain dormancy of potentially autoreactive T cells.
However, mice and humans with disabled Tregs rapidly develop multiorgan autoimmunity and die
young, manifesting polyclonal activation of almost all CD4+ clones. Thus, we hypothesized that
the number of autoreactive clones embedded in the peripheral repertoire can be much higher (i.e.
over one-third of all CD4+ cells) as compared to what is currently anticipated. In Specific Aim 1,
we will examine how the intrathymic expression of different self-peptides supports or prevents an
escape of autoreactive T cells from central tolerance. This approach will document that potentially
self-reactive CD4+ clones commonly trespass to lymphoid organs of B6 mice as quiescent cells.
Next, we will test these cells ex vivo responses to a known set of self-peptides naturally presented
by mouse Ab molecules to determine if these clones are triggered by ubiquitous or specific
autoantigens. In Specific Aim 2, we will investigate why mice expressing single autoantigen
across the body have main autoimmunity manifestation in specific organs and examine the role
of non-classical CD4+ T cells in autoimmunity in this model. In Aim 3 we will use a new single-cell
RNA seq system from 10X Genomics, to examine in individual CD4+ cells their transcriptomes
and native αβTCRs to identify genes targeted by Tregs in potentially autoreactive cells to keep
them dormant and prevent autoimmunity. Overall, this application will revisit the relative
importance of various mechanisms of tolerance in the maintenance of homeostasis to self-
antigens and can reveal new mechanisms of how Tregs control self-reactivity.

## Key facts

- **NIH application ID:** 10072407
- **Project number:** 1R01AI150791-01A1
- **Recipient organization:** GEORGIA STATE UNIVERSITY
- **Principal Investigator:** LESZEK IGNATOWICZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,542
- **Award type:** 1
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072407

## Citation

> US National Institutes of Health, RePORTER application 10072407, Autoreactive CD4 T cells in healthy mice (1R01AI150791-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10072407. Licensed CC0.

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