Lysosomal NKG7 restrains mTORC1 activity to promote CD8+ T cell durability and tumor control
Hyoungjun Ham, Jacob B. Hirdler, Daniel Bihnam, Zhiming Mao, Joanina K. Gicobi, Bruna de 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 Rodrigues Pessoa, Akhilesh Pandey, Hu Li, Fabrice Lucien, Henrique Borges da Silva, Haidong Dong, Daniel D. Billadeau
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. 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.