# Interrogation of T cell Bystander Activation in Scleroderma

> **NIH NIH R03** · YALE UNIVERSITY · 2024 · $147,400

## Abstract

PROJECT SUMMARY
Fibrosis is a common final outcome of most human chronic inflammatory diseases and has been estimated to
contribute to almost half of all deaths in the world1. It can result from autoimmune diseases such as
scleroderma [systemic sclerosis (SSc)] and after stem cell transplant in graft-vs-host disease. SSc and the
sclerodermoid subtype of graft-vs-host disease (sGvHD) most commonly affect the skin and the degree of skin
involvement is associated with higher mortality and internal organ dysfunction2,3, suggesting common
underlying mechanisms. T cells are fundamental regulators of fibrosis pathogenesis in both diseases, but the
mechanisms by which T cells drive fibrosis remain unclear. Mismatch of minor histocompatibility (mHA) alleles
is required for the induction of sGvHD4, but the importance of antigen-independent T cell functions is poorly
understood. This proposal aims to understand how antigen non-related CD4+ T cells contribute to the
pathogenesis of SSc in response to pro-inflammatory cytokines.
In this project, we examine how innate-like functions of CD4+ T lymphocytes regulate skin fibrosis. CD4+ T cells
respond to a specific antigen and differentiate into distinct subsets of helper T cells, including Th1, Th2, and
Th175. However, differentiated CD4+ T cells can respond to IL-1 family cytokines to generate a diverse
cytokine milieu, including IFNγ, IL-13 and IL-17A6. Such bystander activated CD4+ T cells have been shown to
drive autoimmunity in diseases such as multiple sclerosis7. SSc and sGvHD skin are characterized by aberrant
expression of cytokines spanning type 1, 2 and 17 immune responses8-10. We therefore propose that bystander
activation of CD4+ T cells occurs in SSc and sGvHD and to investigate the mechanisms by which it is
generated. To accomplish these goals, we will use sclerodermoid GvHD mouse models, which are the primary
models of SSc skin fibrosis dependent on adaptive immune cells4,11. In our first aim, we will characterize
bystander activation of CD4+ T cells in sGvHD mice by modulating the number of antigen unrelated CD4+ T
cells and measuring their accumulation and cytokine expression profile in relation to fibrosis severity. This will
allow us to establish to what degree bystander activated CD4+ T cells affects skin fibrosis in vivo. In the second
aim, we will examine the cytokine signals that activate CD4+ T cells in this model. We will assess protein levels
of inflammatory cytokines including IL-1 family members in the skin and blood and perform in vitro validation
for their ability to drive expression of effector cytokines and extracellular matrix genes by fibroblasts. Together,
these aims will provide mechanistic insight into how T cells drive the pathogenesis of SSc skin fibrosis, which
may identify new targetable signaling pathways for development of treatments that impact patients’ lives.

## Key facts

- **NIH application ID:** 10789718
- **Project number:** 1R03AR083454-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Ian D Odell
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $147,400
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10789718

## Citation

> US National Institutes of Health, RePORTER application 10789718, Interrogation of T cell Bystander Activation in Scleroderma (1R03AR083454-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10789718. Licensed CC0.

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