# A T cell STAT3-BATF axis regulates intestinal gamma delta T cell homeostasis and disease

> **NIH NIH R21** · PURDUE UNIVERSITY · 2024 · $183,614

## Abstract

PROJECT SUMMARY. A dysregulated intestinal immune response is a hallmark of inflammatory bowel
disease (IBD), but current therapies that target these responses often exhibit poor long-term efficacy. The
reasons for this poor efficacy likely stem from an incomplete understanding of the immunological and microbial
interactions that lead to disease. Recent studies examining immune interactions in human IBD patients have
highlighted dysregulated interactions between immunoregulatory and inflammatory T cells as a key feature of
disease. However, the exact cellular players involved and how these dysregulated interactions occur remain
unclear. In efforts to close these gaps in knowledge, our long-term goals are to define the mechanisms that
govern the interactions between immunoregulatory and inflammatory T cells and how these interactions can be
targeted to improve IBD therapeutics.
 In our preliminary data, we show that mice carrying conventional T cell (i.e. αβ T cell receptor+)-specific
deletions of STAT3 and BATF develop an aggressive spontaneous colitis that closely resembles intestinal
inflammation that is characteristic of human IBD. Intriguingly, the known mediators and suppressors of disease
(IL-17-producing Th17 and Foxp3+ T regulatory (Treg) cells), are equivalent in STAT3/BATF-double deficient
mice and disease-free STAT3 and BATF-single deficient mice. These data suggest that a STAT3/BATF-
regulated transcriptional program induces Th17/Treg-independent immunoregulatory function that is critical for
maintaining intestinal homeostasis. Intestinal disease in conventional T cell STAT3/BATF-deficient mice was
marked by the rapid accumulation of microbiota-dependent inflammatory γδ T cells, resembling those found in
lesional colonic tissues of IBD patients. These data suggest that STAT3/BATF-expressing conventional T cells
interact with the microbiota and γδ T cells to suppress disease. The objective of this study is to determine how
STAT3 and BATF regulate the interactions and functions of conventional immunoregulatory T cells and to
define how microbiota-dependent γδ T cells contribute to disease. Here we hypothesize that conventional T cell
STAT3 and BATF cooperatively regulate a gene network that influences interactions with the microbiota and
pathogenic γδ T cell responses in IBD. We will test this hypothesis via two aims in which we will 1) define the
STAT3/BATF-regulated transcriptional network that governs conventional-γδ T cell interactions in IBD and 2)
determine the role the microbiota-induced γδ T cells in driving IBD. The results of this work will be highly
significant and innovative as we have identified a novel mechanism by which conventional T cells maintain
intestinal homeostasis and developed a new murine model to examine interactions of these cells with the
microbiota and γδ T cells in disease. Further, our studies will provide insight into new therapies that may act to
bolster STAT3/BATF+ conventional T cells to prevent the on...

## Key facts

- **NIH application ID:** 10804693
- **Project number:** 5R21AI176326-02
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Matthew R Olson
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $183,614
- **Award type:** 5
- **Project period:** 2023-03-10 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10804693

## Citation

> US National Institutes of Health, RePORTER application 10804693, A T cell STAT3-BATF axis regulates intestinal gamma delta T cell homeostasis and disease (5R21AI176326-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10804693. Licensed CC0.

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