Mammalian Target of Rapamycin Protein Complex 2 Regulates Differentiation of Th1 and Th2 Cell Subsets via Distinct Signaling Pathways

Abstract

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.

Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system

“…mTORC2‐deficient T cells have decreased activation‐induced binding to ICAM‐1, a key step in the immune response (Lee et al ., 2010). The interaction of T cells with ICAM‐1 is mediated by the integrin lymphocyte function‐associated antigen 1 (LFA1), which consists of two subunits, Cd11a and Cd11b.…”

Regulation of Protein Kinase C function by phosphorylation on conserved and non-conserved sites

“…More recent evidence has demonstrated that the mammalian Target of Rapamycin (mTOR) pathway regulates TM phosphorylation of some, but not all, PKCs [59][60][61]. mTOR is a serine/threonine kinase that associates with other proteins to form multi-protein complexes.…”

“…Indeed, the TM of PKC has been reported to be an autophosphorylation site [54,66]. While deletion of mTORC2-specific components in MEFs appears to have no effect on TM phosphorylation or expression of PKC , this pathway regulates TM phosphorylation of PKC in T lymphocytes [61]. A role for the mTORC2 pathway in PKC phosphorylation in T cells but not in MEFs highlight the fact that regulatory inputs that influence PKC function are likely not just to be isoform but also cell type specific.…”

“…For example, inducible phosphorylation has been reported for cPKCs (at all three sites) [86][87][88], nPKCs (at all three sites) [89][90][91]61] and aPKCs (PKC on its A-loop site) …”

“…While cPKCs were initially reported to autophosphorylate at both the TM and HM [57], the mTORC2 complex has also been implicated in HM phosphorylation of PKC in MEFs [71,72,59], while mTORC2 also influences PKC phosphorylation at this site in T lymphocytes [61]. Interestingly, while the levels of expression of PKC are unaffected following deletion of mTORC2 components in MEFs [59,60], phosphorylation of PKC (and PKC * ) at the HM motif is sensitive to rapamycin treatment in human embryonic kidney cells, which therefore implicates the mTORC1 complex in phosphorylation of these isoforms [73,66].…”