Summary Many functions of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) have been defined, but relatively little is known about the biology of an alternative mTOR complex, mTORC2. We showed that conditional deletion of rictor, an essential subunit of mTORC2, impaired differentiation into T helper 1 (Th1) and Th2 cells without diversion into FoxP3+ status or substantial effect on Th17 cell differentiation. mTORC2 promoted phosphorylation of protein kinase B (PKB, or Akt) and PKC, Akt activity, and nuclear NF-κB transcription factors in response to T cell activation. Complementation with active Akt restored only T-bet transcription factor expression and Th1 cell differentiation, whereas activated PKC-θ reverted only GATA3 transcription factor and the Th2 cell defect of mTORC2 mutant cells. Collectively, the data uncover vital mTOR – PKC and mTOR–Akt connections in T cell differentiation, and reveal distinct pathways by which mTORC2 regulates development of Th1 and Th2 cell subsets.

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Rictor is essential in Notch-driven T-ALL pathogenesis.

T helper type 1 (Th1) and Th2 cells have critical roles in the development of cell-mediated and humoral immune responses, respectively. This division of function predicts that Th1 cells mediate inflammatory diseases and Th2 cells promote antibody (Ab)-mediated autoimmunity. Our previous studies using HEK-293 cells expressing the extracellular domain of the TSH receptor (TSHR) showed that Stat4-/- mice, which lack Th1 cells, are susceptible, whereas Stat6-/- mice, which lack Th2 cells, are resistant to the induction of Graves' hyperthyroidism. To investigate the role of Stat4 and Stat6 genes in other murine models of hyperthyroidism, we injected wild-type BALB/c, Stat4-/-, and Stat6-/- mice with an adenovirus expressing amino acid residues 1-289 of TSHR (TSHR-289-ad or 289-ad). The viral system induces a much stronger immune response with much more rapid onset of disease. Our results showed that 56% of wild-type, 75% of Stat4-/-, and 39% of Stat6-/- mice developed hyperthyroidism. Hyperthyroid mice exhibited thyroid stimulatory Abs. The Stat4-/- mice developed a higher incidence and greater severity of hyperthyroidism compared with wild-type and Stat6-/- mice. BALB/c and Stat4-/- mice showed significantly higher TSHR Abs of the IgG1 subclass and IL-4 compared with Stat6-/- mice. In contrast, Stat6-/- mice had predominantly the IgG2a subclass of TSHR Ab and produced significantly higher amounts of IFN-gamma than BALB/c and Stat4-/- mice. All hyperthyroid mice showed enlarged thyroid glands with hyperactivity. These results suggest that in the TSHR-289-ad model, the Th2 cells are more efficient in mediating disease, but in the absence of Th2 cells, Th1 cells may still initiate a reduced incidence of Graves' hyperthyroidism.