Roles of mTORC1 and mTORC2 in controlling gamma delta T1 and gamma delta T17 differentiation and function

摘要

The metabolism-controlled differentiation of alpha beta T cells has been well documented; however, the role of a metabolism program in gamma delta T cell differentiation and function has not been clarified. Here, using CD2-cre; mTORC1 Raptor-f/f, and mTORC2 Rictor-f/f mice (KO mice), we found that mTORC1, but not mTORC2, was required for the proliferation and survival of peripheral gamma delta T cells, especially V gamma 4 gamma delta T cells. Moreover, mTORC1 was essential for both gamma delta T1 and gamma delta tau 17 differentiation, whereas mTORC2 was required for gamma delta T17, but not for gamma delta tau 1, differentiation. We further studied the underlying molecular mechanisms and found that depletion of mTORC1 resulted in the increased expression of SOCS1, which in turn suppressed the key transcription factor Eomes, consequentially reducing IFN-gamma production. Whereas the reduced glycolysis resulted in impaired gamma delta tau 17 differentiation in Raptor KO gamma delta T cells. In contrast, mTORC2 potentiated gamma delta tau 17 induction by suppressing mitochondrial ROS (mitoROS) production. Consistent with their cytokine production profiles, the Raptor KO gamma delta T cells lost their anti-tumor function both in vitro and in vivo, whereas both Raptor and Rictor KO mice were resistant to imiquimod (IMQ)-induced psoriasis-like skin pathogenesis. In summary, we identified previously unknown functions of mTORC1 and mTORC2 in gamma delta T cell differentiation and clarified their divergent roles in mediating the activity of gamma delta T cells in tumors and autoimmunity.