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

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

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract 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.

Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56931-6

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DOI: 10.1038/s41467-025-56931-6

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