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<p>During infection and cancer, mTORC1-mediated metabolic regulation impacts CD8<sup>+</sup> T cell effector expansion and memory development. However, the mechanisms by which CD8<sup>+</sup> T cells regulate mTORC1 to support their unique metabolic requirements remain unknown. Here we show that NKG7, a lysosomal protein whose expression is restricted to cytotoxic lymphocytes, negatively regulates mTORC1 recruitment and activation by inhibiting assembly and function of the lysosomal proton pump, vacuolar ATPase (v-ATPase). Human and mouse CD8<sup>+</sup> T cells lacking NKG7 show more acidic lysosomes and increased activation of mTORC1 signaling, which could be reversed by inhibition of v-ATPase activity. In mice responding to LCMV infection, NKG7-deleted effector CD8<sup>+</sup> T cells are less durable and generate fewer memory precursors, whereas induced expression of NKG7 in CD8<sup>+</sup> T cells results in increased presence of intra-tumoral T cells. Overall, our work identifies NKG7 as a CD8<sup>+</sup> T cell-specific regulator of mTORC1 activity, required for optimal immune responses.</p>

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Lysosomal NKG7 restrains mTORC1 activity to promote CD8+ T cell durability and tumor control

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月14日

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  • Hyoungjun Ham,
  • Jacob B. Hirdler,
  • Daniel T. Bihnam,
  • Zhiming Mao,
  • Joanina K. Gicobi,
  • Bruna Gois Macedo,
  • Maria F. Rodriguez-Quevedo,
  • Destiny F. Schultz,
  • Cristina Correia,
  • Jun Zhong,
  • Kodi E. Martinez,
  • Alma Banuelos,
  • Dallin S. Ashton,
  • Anthony B. Lagnado,
  • Ruifeng Guo,
  • Rodrigo Pessoa,
  • Akhilesh Pandey,
  • Hu Li,
  • Fabrice Lucien,
  • Henrique Borges da Silva,
  • Haidong Dong,
  • Daniel D. Billadeau

摘要

During infection and cancer, mTORC1-mediated metabolic regulation impacts CD8+ T cell effector expansion and memory development. However, the mechanisms by which CD8+ T cells regulate mTORC1 to support their unique metabolic requirements remain unknown. Here we show that NKG7, a lysosomal protein whose expression is restricted to cytotoxic lymphocytes, negatively regulates mTORC1 recruitment and activation by inhibiting assembly and function of the lysosomal proton pump, vacuolar ATPase (v-ATPase). Human and mouse CD8+ T cells lacking NKG7 show more acidic lysosomes and increased activation of mTORC1 signaling, which could be reversed by inhibition of v-ATPase activity. In mice responding to LCMV infection, NKG7-deleted effector CD8+ T cells are less durable and generate fewer memory precursors, whereas induced expression of NKG7 in CD8+ T cells results in increased presence of intra-tumoral T cells. Overall, our work identifies NKG7 as a CD8+ T cell-specific regulator of mTORC1 activity, required for optimal immune responses.