# Tcf/Lef and B-catenin pathway in follicular helper T cells

> **NIH NIH R01** · HACKENSACK UNIVERSITY MEDICAL CENTER · 2020 · $441,535

## Abstract

The vast majority of currently licensed human vaccines work on the basis of long-term protective
antibody responses. T follicular helper (Tfh) cells are CD4+ T cells specialized in providing help to B cells,
particularly within germinal centers (GCs). With Tfh cells delivering help signals via costimulatory molecules
and cytokines, B cells undergo somatic hypermutation and affinity maturation within GCs, generating plasma
cells and memory B cells and with greater protective efficacy. Tfh cells are also found in great abundance in
peripheral blood of patients with systemic lupus erythematosus and myasthenia gravis, suggesting a role of Tfh
cells in pathogenic autoantibody production. Therefore, increasing our knowledge of Tfh cell development and
function in normal and aberrant immune responses will aid design of more efficacious vaccines against
infectious diseases and discovery of novel therapeutic approaches to treat autoimmunity.
 Tcf1 and Lef1 transcription factors are essential for normal T cell development and are known to
interact with the β-catenin coactivator for gene regulation. Previously we showed Tcf1 and Lef1 critically
regulate longevity and maturation of memory CD8+ T cells. We conditionally ablated both genes in mature T
cells to bypass the impact on thymocyte development, and showed Tcf1 and Lef1 are also essential for Tfh
differentiation. Our recent ChIPseq mapping of the Tcf1 cistrome in Tfh cells revealed it is broadly associated
with the Tfh genetic program, beyond the reported Bcl6-Blimp1 axis. We also made a surprising finding that
Tcf1 and Lef1 are not only transcriptional regulators but also have intrinsic histone deacetylase (HDAC)
activity. These unexpected findings led us to hypothesize that Tcf1 and Lef1 couple the intrinsic HDAC
activity with their β-catenin- and DNA-binding capacity to shape the enhancer landscape,
transcriptional programs, and functionality of Tfh cells. Our specific aims are:
Specific Aim 1. To determine how Tcf1 and Lef1 control enhancer organization and transcriptional
programming during effector Tfh differentiation..
Specific Aim 2. To investigate the necessity and sufficiency of β-catenin pathway in Tfh differentiation.
 This application will use viral infection models to systematically investigate Tcf1/Lef1 transcription
factors, β-catenin coactivator, and their interaction as novel regulators of Tfh differentiation at the initiation,
effector and memory phases. It is particularly exciting that Tcf1 and Lef1 directly bridge transcriptional and
epigenetic regulation in Tfh cells, which will establish a new paradigm in coordination of genetic and epigenetic
regulation. These studies will thus provide rationales for utilizing the Tcf1/Lef1-β-catenin pathway to enhance
Tfh functions for more effective vaccines or to dampen Tfh activities for treating autoimmune diseases.

## Key facts

- **NIH application ID:** 10123683
- **Project number:** 7R01AI121080-05
- **Recipient organization:** HACKENSACK UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Weiqun Peng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $441,535
- **Award type:** 7
- **Project period:** 2016-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123683

## Citation

> US National Institutes of Health, RePORTER application 10123683, Tcf/Lef and B-catenin pathway in follicular helper T cells (7R01AI121080-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10123683. Licensed CC0.

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