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

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.