PTEN regulates natural killer cell trafficking and effector functions (IRM7P.484)

Abstract

Abstract Phosphatase and tensin homolog (PTEN) is a critical negative regulator of the PI3 kinase pathway, members of which are essential for regulating natural killer (NK) cell signaling and activation. To evaluate whether PTEN was required for normal NK cell functions, we utilized a mouse model of NK specific PTEN deficiency (Ncr1iCre knockin x PTENflox). PTEN deletion resulted in significant loss of NK cells in the bone marrow and other lymphoid tissues, but markedly increased numbers within the peripheral blood and lung. Surprisingly, we observed near equivalent NK cell maturation within peripheral organs regardless of PTEN expression, suggesting that PTEN operates to re-distribute NK cells during development. Similarly, despite impaired migration to chemoattractants in vitro, PTEN-deficient NK cells egress more efficiently from the bone marrow and preferentially reside in sinusoidal compartments, but are specifically retained in the lung and peripheral vasculature. Given the inappropriate localization in the absence of PTEN, we further evaluated whether cytotoxic functions were altered. While PTEN deficient NK cells have enhanced cytotoxicity against co-localized RMAS tumors, they are unable to migrate to distal tumor sites. These data suggest that PTEN is required for the trafficking of NK cells during both homeostasis and in the presence of malignancy, during which it represses cytotoxic functions.