TIPE2 is a checkpoint in natural killer cell maturation and anti-tumor immunity

The maturation process determines NK cell functionality. We verified that tumor necrosis factor-alpha-induced protein-8 like-2 (TIPE2) works as a potent negative regulator in NK cell maturation. We found that TIPE2 expression gradually increased during NK cell ontogenesis correlating to their maturation stages in mice. NK-specific TIPE2 deficiency resulted in increased number of mature NK cells. To further confirm the role of TIPE2 in NK cell maturation, we performed single-cell RNA sequencing. Based on the key gene expression of NK cell effector molecules, transcriptional factors, maturation markers, and proliferation marker, we identified NK cell maturation program as Cluster#1->Cluster#2->Cluster#0 by which immature NK cells should go through to gain optimal effector functions at the cost of proliferation ability. According to this model, NK-specific TIPE2 deficient mice contained more NK cells belonging to the terminally mature Cluster#0 than control mice (up to 10% more), which is consistent with what we observed by flow cytometry. Therefore, these results collectively showed that NK-specific TIPE2 deficiency promotes NK cell maturation. Single-cell RNAseq of 6-week old NK-specific TIPE2 deficient mice and control mice