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<p>Progenitor CD8<sup>+</sup> 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<sup>+</sup> T cell effector differentiation. ZFP148-deficient CD8<sup>+</sup> T cells displayed increased frequency of cytolytic effector cells and reduced frequency of exhausted cells compared with <i>Zfp148</i><sup>fl/fl</sup> 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<sup>+</sup> T cells synergized with programmed cell death-1 blockade to improve tumor control in syngeneic mouse models. Consistently, cancer patients with lower <i>ZNF148</i> expression in tumor-infiltrating CD8<sup>+</sup> T cells showed improved responsiveness to immunotherapies. Collectively, our study identifies ZFP148 as a transcriptional repressor of CD8<sup>+</sup> T cell effector differentiation and highlights its therapeutic potential for enhancing antitumor immunity.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月27日

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  • Tong Xiao,
  • Xingyu Chen,
  • No-Joon Song,
  • Ryan J. Brown,
  • Anjun Ma,
  • Jay K. Mandula,
  • Amir Yousif,
  • Yi Wang,
  • Minh Quynh May Le,
  • Jianying Li,
  • Fengxia Gao,
  • Bella Weaver,
  • Heng-Yi Chen,
  • Fang-Yun Lay,
  • Debasish Sundi,
  • Maria Velegraki,
  • Payton Weltge,
  • Juanita L. Merchant,
  • Mark P. Rubinstein,
  • Kenneth J. Oestreich,
  • Chan-Wang Jerry Lio,
  • Hazem E. Ghoneim,
  • Xue Li,
  • Dan Theodorescu,
  • Gang Xin,
  • Qin Ma,
  • Weiguo Cui,
  • Zihai Li

摘要

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.