# Molecular mechanisms of CD8 T cell fate decision instructed by cytokine signaling

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $583,619

## Abstract

Abstract
In response to viral infection or vaccination, antigen(Ag)-specific CD8 T cells that are present at low
frequencies undergo rapid clonal expansion. While the majority of activated CD8 T cells become terminally
differentiated effector T (T ECF) cells following expansion and die after Ag clearance, a small fraction of them
persists as memory cells (Tr,1er,:) that contribute to long-term protection. However, it remains incompletely
understood how cell-extrinsic stimuli through TCR and cytokine receptors establish the gene regulatory
networks that determine the fates of activated CD8 T cells. The overall goal of this grant is to dissect the
molecular and cellular mechanisms by which TCR and IL-2R signaling cooperatively regulates CD8 T cell
differentiation through the control of the critical transcription factor TCF-1 encoded by Tcf7_ We will test the
hypothesize that cooperative action between signals induced by antigen and IL-2, but not IL-15, specifically
during priming induces expression of a set of transcription factors and epigenetic changes at a transcriptional
silencer element in the Tcf7 locus. The establishment of stable Tcf7 repression requires the stimulationresponsive
enhancement of IL-2R signaling, which establishes steady the TEFF- or T MEM-specific gene
regulatory circuitry that can be stably maintained after the inducing cell extrinsic stimuli decays as immune
responses resolve or become equilibrated. These studies will provide insights into the long standing question
of the molecular mechanisms of CD8 T cell differentiation and potential application to programming improved
immunotherapies.

## Key facts

- **NIH application ID:** 10824683
- **Project number:** 1R01AI176664-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Takeshi Egawa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $583,619
- **Award type:** 1
- **Project period:** 2023-12-01 → 2028-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10824683

## Citation

> US National Institutes of Health, RePORTER application 10824683, Molecular mechanisms of CD8 T cell fate decision instructed by cytokine signaling (1R01AI176664-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10824683. Licensed CC0.

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