SUMMARY Effector T cell differentiation requires the simultaneous integration of multiple, and sometimes opposing, cytokine signals. We demonstrate that mTOR plays a role in dictating the outcome of T cell fate. mTOR deficient T cells display normal activation and IL-2 production upon initial stimulation. However, such cells fail to differentiate into Th1, Th2 or Th17 effector T cells under skewing conditions. The inability to differentiate is associated with a decrease in STAT activation and failure to upregulate lineage specific transcription factors. Under all normally activating conditions, T cells lacking mTOR differentiate into Foxp3+ regulatory cells. This differentiation is associated with hyperactive Smad3 activation in the absence of exogenous TGF-β. Surprisingly, T cells in which TORC1 activity has been selectively deleted do not divert to a regulatory T cell pathway, revealing an unappreciated role for TORC2 signaling in preventing the generation of regulatory T cells. Overall our studies suggest that differential TORC1 and TORC2 signaling regulate decisions between effector and regulatory T cell lineage commitment.

mTOR has emerged as an important regulator of T helper cell differentiation. Here we demonstrate that TH1 and TH17 differentiation is selectively regulated by Rheb-dependent mTOR complex 1 (mTORC1) signaling. Rheb-deficient T cells fail to generate TH1 and TH17 responses in vitro and in vivo and cannot induce classical experimental autoimmune encephalomyelitis (EAE). However, they retain their ability to become TH2 cells. Alternatively, when mTORC2 signaling is deleted in T cells, they fail to generate TH2 cells in vitro and in vivo but preserve their ability to become TH1 and TH17 cells. Our data provide mechanisms by which the two distinct signaling pathways downstream of mTOR differentially regulate helper cell fate. These findings define a novel paradigm linking T cell differentiation with selective metabolic signaling pathways.

NMDA receptors are linked to intracellular cytoskeletal and signaling molecules via the PSD-95 protein complex. We report a novel family of postsynaptic density (PSD) proteins, termed Shank, that binds via its PDZ domain to the C terminus of PSD-95-associated protein GKAP. A ternary complex of Shank/GKAP/PSD-95 assembles in heterologous cells and can be coimmunoprecipitated from rat brain. Synaptic localization of Shank in neurons is inhibited by a GKAP splice variant that lacks the Shank-binding C terminus. In addition to its PDZ domain, Shank contains a proline-rich region that binds to cortactin and a SAM domain that mediates multimerization. Shank may function as a scaffold protein in the PSD, potentially cross-linking NMDA receptor/PSD-95 complexes and coupling them to regulators of the actin cytoskeleton.