MTORC2 controls Th9 polarization and allergic airway inflammation.

Abstract

T helper type 9 (Th9) cells, a subpopulation of CD4+ T cells, play a critical role in the pathogenesis of allergic airway inflammation. However, it remains unknown whether mTORC2 regulates Th9 differentiation or function during allergic inflammation. T-cell-specific Rictor-deficient mice, a mouse model of allergic airway inflammation induced by ovalbumin (OVA) sensitization and a mouse model of adoptive transfer of induced Th9 cells, were used to address the roles of mTORC2 in the pathogenesis of allergic airway inflammation. The invitro Th9 induction, multiple colors flow cytometry, real-time PCR, and Western blots were used to investigate the molecular effects of mTORC2 in Th9 induction. The differentiation of naïve CD4+ T cells into Th9 cells was significantly diminished in the absence of Rictor, the core component of mTORC2. Using a mouse model of allergic airway inflammation induced by OVA sensitization, T-cell-specific Rictor-deficient mice show much less severe allergic airway inflammation characterized by decreased pathological alterations and fibrosis of the lungs, which was accompanied with reduced Th9 differentiation and infiltration. Importantly, the isolated Rictor-deficient Th9 cells mediate less severe allergic pathogenesis upon adoptive transfer. Rictor deficiency impairs Th9 cell differentiation by reducing IRF4 expression rather than affecting Foxo1/Foxo3a transcriptional activity, which is likely due to decreased Akt and/or STAT6 activation. These findings uncover a novel role of mTORC2 in Th9 cell differentiation and may have important implications for therapeutic intervention of allergic diseases.