# Endogenous retroviruses in autoimmunity: T cell repertoire, tolerance, and disease

> **NIH AR R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2026 · $504,117

## Abstract

PROJECT SUMMARY
 Rheumatoid Arthritis (RA) is a chronic, destructive autoimmune disease that primarily targets joints. It affects
millions globally and is associated with both disability and reduced lifespan. Antigen-dependent activation of
CD4 T cells contributes to disease onset. However, the specific antigens that activate CD4 T cells and the
mechanisms by which they evade tolerance remain undefined. Therefore, our long-term goal is to identify the
earliest events that activate self-reactive T cells and define the mechanisms they employ to subvert tolerance.
This knowledge may reveal vulnerabilities in disease-causing T cells that could lead to new diagnostic and
therapeutic interventions.
 To identify the early mechanistic events that break T cell tolerance, we use the SKG mouse model in which a
hypomorphic Zap70 kinase allele impairs TCR signaling; this deficit allows autoreactive thymocytes to escape
negative selection, leading to mature autoreactive T cells that cause autoimmune arthritis resembling RA. Our
group identified a subset of highly arthritogenic CD4 T cells in these mice. This subset of CD4 T cells is
enriched for T cells that recognize superantigens (Sags) from an endogenous retrovirus (ERV) known as the
mouse mammary tumor virus (MMTV).
 ERVs are implicated in human autoimmune disease, but determining their causal role has been
exceptionally difficult. Our preliminary data indicate that these Sag-reactive T cells, which are normally deleted
in the thymus of wild-type mice, escape deletion in SKG mice, accumulate in arthritic joints, and contribute to
disease pathogenesis. These findings suggest that ERVs may play a crucial role in initiating and sustaining
autoimmune responses. Furthermore, we find a similar process may be occurring in human RA synovial tissue.
 The central hypothesis of this proposal is that ERV Sags break immune tolerance and drive RA by
persistently engaging and activating self-reactive T cells. To test this, we will use genet

## Key facts

- **NIH application ID:** 11361713
- **Project number:** 5R01AR084520-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Judith  Ashouri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** AR
- **Fiscal year:** 2026
- **Award amount:** $504,117
- **Award type:** 5
- **Project period:** 2025-07-01T00:00:00 → 2030-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11361713

## Citation

> US National Institutes of Health, RePORTER application 11361713, Endogenous retroviruses in autoimmunity: T cell repertoire, tolerance, and disease (5R01AR084520-02). Retrieved via AI Analytics 2026-07-07 from https://api.ai-analytics.org/grant/nih/11361713. Licensed CC0.

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