# Epigenetic regulation of T cell differentiation during infection

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $565,557

## Abstract

PROJECT SUMMARY
In chronic infection and cancer, CD8 T cells differentiate into an epigenetically distinct, dysfunctional lineage
referred to as exhausted T cells. Through use of in vivo genetic screens and genetic mouse models, we have
generated preliminary evidence that epigenetic regulators of the bromodomain and extraterminal domain (BET)
family orchestrate CD8 T cell differentiation and exhaustion during infection. The BET family is composed of
highly druggable chromatin readers BRD2, BRD3, BRD4, and germ cell-restricted BRDT. First-generation pan-
BET inhibitors (BETi) have been evaluated clinically for cancers and inflammatory diseases, and have garnered
considerable interest for the treatment of infections. However, BETi clinical trials have, so far, yielded mixed
results. A critical roadblock to improving BETi therapy is the lack of a detailed molecular understanding of the
function of each individual BET protein in the immune system. This proposal seeks to define how BET proteins
intrinsically regulate T cell exhaustion, which is crucial for advancing our fundamental understanding of
epigenetic regulation of T cell differentiation and for optimizing BETi strategies to reprogram exhaustion.
Accordingly, our preliminary data indicate that BET proteins have discrete, non-redundant roles in regulating
CD8 T cell differentiation and stemness in vivo. We have also found that a tailored, finite BETi treatment strategy
may allow for efficient exhaustion reprogramming and optimal T cell function. Here, we will use inducible genetic
depletion strategies to pinpoint the intrinsic role of each BET protein in controlling T cell fate during chronic
infection, and we will investigate whether precisely timed treatment with second-generation BETi targeting
individual BET proteins effectively modulates exhaustion. Last, despite widespread therapeutic interest in
epigenetically reprogramming exhausted cells, epigenetic mechanisms governing T cell exhaustion remain to
be fully elucidated. Based on preliminary findings, we will investigate whether BRD4 promotes exhaustion
through remobilizing to exhaustion-specifying enhancer regions. We hypothesize that BRD2, BRD3, and BRD4
coordinate CD8 T cell differentiation into an exhausted state, and BETi treatment can be optimized to restore
function to exhausted cells during chronic infection. We propose to: Aim 1, determine the role of BRD4 in
controlling the differentiation and stability of exhausted CD8 T cells during chronic infection. Aim 2, define the
role of BRD4 in regulating the function of exhaustion-specific enhancer elements in CD8 T cells. Aim 3, assess
BRD2 and BRD3 as novel regulators of T cell exhaustion and investigate the impact of BET inhibition on CD8 T
cell differentiation during chronic infection. Resolving the roles of BET proteins in exhaustion has broad
implications for understanding fundamental epigenetic control of T cell differentiation, the immunological
consequences of BETi, and may re...

## Key facts

- **NIH application ID:** 10883154
- **Project number:** 1R01AI177864-01A1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** John Justin Milner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $565,557
- **Award type:** 1
- **Project period:** 2024-06-18 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883154

## Citation

> US National Institutes of Health, RePORTER application 10883154, Epigenetic regulation of T cell differentiation during infection (1R01AI177864-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10883154. Licensed CC0.

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