# Tcf1 programs CD8 T cell responses to enhance viral and cancer immunity

> **NIH NIH R01** · HACKENSACK UNIVERSITY MEDICAL CENTER · 2020 · $542,495

## Abstract

CD8+ T lymphocytes are essential players in mounting protective cellular immune responses against
pathogens and malignantly transformed cells. Depending on the nature of antigen challenge, CD8+ T cells are
equipped with certain levels of plasticity to maximize reduction of infected or tumor cells. After pathogen
clearance resulting from acute infections, memory CD8+ T cells persist for long term and provide enhanced
protection against the same or related pathogens, and these features constitute the basis for prophylactic
vaccines. On the other hand, antigen persistence, as a result of chronic infection and cancers, causes CD8+ T
cell exhaustion or dysfunction; nonetheless, the exhausted CD8+ T (Tex) cells can be partly reinvigorated, as
seen in recent success of checkpoint blockade in cancer immunotherapy.
Understanding molecular circuits that underlie T cell memory and exhaustion is critical for fully harnessing the
potentials of cytotoxic CD8+ T cells for improving viral or cancer immunity. In this competitive renewal
application, our goal is to uncover the uncharted links of Tcf1 and its HDAC activity with chromatin accessibility
and chromatin looping-based enhancer-promoter interactions in memory and exhausted CD8+ T cells. The
specific aims are as follows:
Aim 1. To investigate how Tcf1 preprograms enhanced recall responses by memory CD8+ T cells.
Memory CD8+ T cells exhibit enhanced recall response by more robust proliferation and more rapid activation
of cytolytic activities than naïve T cells. A major knowledge gap remains regarding the molecular basis and
molecular regulators that underlie the heightened immune response. We hypothesize that Tcf1 preprograms
central memory CD8+ T cells for their enhanced responsiveness to recall stimulation. We will use unbiased
systems biology approaches including DNase-seq and HiC to define how Tcf1 and its HDAC activity control
chromatin accessibility and looping. Combined with comprehensive functional studies, we will perform in-depth
dissection of the unique molecular wiring that dictates enhanced recall responses by Tcm cells.
Aim 2. To determine the capacity of Tcf1 to enhance functional restoration of exhausted CD8+ T cells.
Recent advances revealed that Tex cells elicited by chronic infection contain a CXCR5+Tim3– subset that has
stem cell-like self-renewing capacity and expresses an elevated level of Tcf1. We hypothesize that Tcf1-
dependent regulatory circuits can be utilized to durably enhance Tex functional restoration. We will test various
Tcf1 forms and cofactor combinations in chronic viral infection and tumor models, and determine their impact
on chromatin accessibility/looping and its link to favorable functional output by Tex cells.
This proposal will mechanistically elucidate how Tcf1 orchestrates 3D-genome to program memory CD8+ and
exhausted CD8+ T cells for enhanced functional output, and provide timely, much needed insights into devising
more effective vaccines and therapeutics for...

## Key facts

- **NIH application ID:** 10069737
- **Project number:** 2R01AI112579-05A1
- **Recipient organization:** HACKENSACK UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Hai-Hui Xue
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $542,495
- **Award type:** 2
- **Project period:** 2015-03-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10069737

## Citation

> US National Institutes of Health, RePORTER application 10069737, Tcf1 programs CD8 T cell responses to enhance viral and cancer immunity (2R01AI112579-05A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10069737. Licensed CC0.

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