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<p>The development and functional maintenance of CD8<sup>+</sup> T cells are metabolically regulated processes in which mitochondria serve as the central hub. Here, we identify glucose-regulated protein 75 (GRP75) as a critical mitochondrial regulator controlling these processes. Using T cell-specific <i>Hspa9</i> (encodes GRP75) knockout mice, we demonstrate that GRP75 deficiency disrupts CD8<sup>+</sup> T cell fate, leading to defective T cell homeostasis and impaired memory differentiation. Mechanistically, impaired mitochondrial function in GRP75-deficient CD8<sup>+</sup> T cells leads to perturbation of IL-7R signaling and aberrant expression of effector-associated molecules. Further studies reveal that GRP75 deficiency leads to upregulation of interferon regulatory factor 4 (IRF4), a critical transcription factor for effector versus memory fate, which in turn suppresses memory CD8<sup>+</sup> T cell differentiation. Our findings establish GRP75 as a pivotal mitochondrial checkpoint that coordinates metabolic state and functional fate in CD8<sup>+</sup> T cells.</p>

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GRP75 sustains CD8+ T cell homeostasis and memory generation through ensuring mitochondrial fitness

  • 期刊论文

  • 发表日期：

    2026年7月31日

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  • Fan Zhao,
  • Pengfei Wang,
  • Zejin Cui,
  • Zhishan Zhao,
  • Lize Wu,
  • Rui Zhang,
  • Dale Gao,
  • Jiayan Wu,
  • Yuwen Shao,
  • Xuexiao Jin,
  • Yadan Bai,
  • Kaixiang Zhu,
  • Linrong Lu

摘要

The development and functional maintenance of CD8+ T cells are metabolically regulated processes in which mitochondria serve as the central hub. Here, we identify glucose-regulated protein 75 (GRP75) as a critical mitochondrial regulator controlling these processes. Using T cell-specific Hspa9 (encodes GRP75) knockout mice, we demonstrate that GRP75 deficiency disrupts CD8+ T cell fate, leading to defective T cell homeostasis and impaired memory differentiation. Mechanistically, impaired mitochondrial function in GRP75-deficient CD8+ T cells leads to perturbation of IL-7R signaling and aberrant expression of effector-associated molecules. Further studies reveal that GRP75 deficiency leads to upregulation of interferon regulatory factor 4 (IRF4), a critical transcription factor for effector versus memory fate, which in turn suppresses memory CD8+ T cell differentiation. Our findings establish GRP75 as a pivotal mitochondrial checkpoint that coordinates metabolic state and functional fate in CD8+ T cells.