# ZFP148 is a transcriptional repressor of cytolytic effector CD8+ T cell differentiation

## TL;DR

This study shows that ZFP148 limits the development of CD8+ T cells into cytolytic effectors and that reducing ZFP148 improves antitumor immunity.

## Contribution

The study identifies ZFP148 as a novel transcriptional repressor of CD8+ T cell effector differentiation and a potential therapeutic target.

## Key findings

- ZFP148-deficient CD8+ T cells show increased cytolytic effector cells and reduced exhaustion during chronic viral infection.
- ZFP148 represses KLF2 expression and limits chromatin accessibility of effector-driving transcription factors.
- ZFP148 ablation in CD8+ T cells synergizes with PD-1 blockade to improve tumor control in mouse models.

## Abstract

Progenitor CD8+ T cells differentiate into effector and exhausted progenies during chronic antigen stimulation; however, mechanisms that restrain exhaustion and sustain effector differentiation remain incompletely defined. Here we identified the transcription factor ZFP148 as a repressor of CD8+ T cell effector differentiation. ZFP148-deficient CD8+ T cells displayed increased frequency of cytolytic effector cells and reduced frequency of exhausted cells compared with Zfp148fl/fl controls during chronic viral infection. Mechanistically, ZFP148 limited the chromatin accessibility of effector-driving transcription factor motifs and directly repressed expression of the transcription factor KLF2. Furthermore, conditional ZFP148 ablation in CD8+ T cells synergized with programmed cell death-1 blockade to improve tumor control in syngeneic mouse models. Consistently, cancer patients with lower ZNF148 expression in tumor-infiltrating CD8+ T cells showed improved responsiveness to immunotherapies. Collectively, our study identifies ZFP148 as a transcriptional repressor of CD8+ T cell effector differentiation and highlights its therapeutic potential for enhancing antitumor immunity.

Li and colleagues show that the transcription factor ZFP148 restrains the differentiation of antigen-specific CD8+ T cells toward cytolytic effector cells by repressing the expression of KLF2.