# Epigenetic programming of T follicular helper cell differentiation

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $581,699

## Abstract

Project Summary
T follicular helper cells (Tfh) are a specialized subset of T cells that directly provide help to B cells to form
germinal centers. Within germinal centers, B cells undergo affinity maturation of antibodies, class switching,
and differentiation of long-lived plasma cells and memory B cells. T follicular helper responses are vital to
long-lived antibody-mediated immune protection, which is demonstrated by the absence of long-lived antibody
responses and the presentation of immune deficiency in Tfh-deficient individuals and animals. Following
activation of naïve CD4 T cells by viral infection or immunization, these newly activated T cells interpret various
signals that induce transcription factors that direct specific gene expression changes. In coordination with
these gene expression changes that occur during T helper cell differentiation, genes undergo DNA methylation
changes at CpG motifs in regulatory elements that control expression or relevant genes. DNA methylation acts
as a repressive epigenetic mark, and the process of demethylation is associated with the ability to express
genes important for cell function. Changes in methylation are catalyzed by Tet dioxygenases that participate in
the processes of demethylation, and DNA methyltransferases that promote new (de novo) methylation to turn
off irrelevant genes. The broad objectives of the specific aims in this proposal are to gain understanding of how
T follicular helper cells undergo DNA methylation programing, either through demethylation or de novo
methylation, and whether manipulation of such programing can enhance or impair T follicular helper cell
function and thus influence antibody responses to vaccination or infection. The specific aims for this proposal
are: Aim 1) Determine the role of Tet2 in regulating the balance of T follicular helper and Th1 cell and memory
cell differentiation; Aim 2) Define the role of de novo methylation in regulating Tfh and Th1 memory cell
differentiation and lineage commitment; and Aim 3) Determine whether DNA methyltransferase inhibition can
promote Tfh differentiation and enhance antibody-mediated immune protection following immunization against
influenza challenge. These studies will utilize cellular immunology approaches, gene expression and whole
genome DNA methylation analyses, and immunization and infectious disease challenge to evaluate the
importance of DNA methylation programing in T follicular helper cell differentiation, function, and memory
formation. Together, these aims will combine to provide a mechanistic evaluation of how T follicular helper
cells differentiate and identify and characterize novel pathways that can be targeted to generate more effective
vaccination strategies that can improve long-lasting immunity.

## Key facts

- **NIH application ID:** 10186686
- **Project number:** 5R01AI137238-04
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Jeffrey Scott Hale
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $581,699
- **Award type:** 5
- **Project period:** 2018-07-06 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10186686

## Citation

> US National Institutes of Health, RePORTER application 10186686, Epigenetic programming of T follicular helper cell differentiation (5R01AI137238-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10186686. Licensed CC0.

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