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

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. Although effector activity and memory formation in CD8 + T cells are known to depend on mTORC1-mediated metabolic regulation, the molecular mechanisms involved are lesser known. Here authors show that NKG7, a lysosomal protein specifically expressed in CD8 + T cells, inhibits mTORC1 function via the lysosomal proton pump, vacuolar ATPase, promoting antitumor activity and expansion of memory T cell precursors.