T cells proliferate in response to strong agonist-induced stimulation of the TCR and costimulatory signaling via CD28. This process is known to depend on the cellular metabolic regulator kinase mTORC1. In Science Signaling, Kane and colleagues show that the activation of mTORC1 in CD4+ T cells in response to TCR signaling involves the adaptor Carma1 and the paracaspase Malt1 but, unexpectedly, not the associated adaptor Bcl-10 or their downstream effector kinase IKK. Loss of Carma1 or Malt1 or inhibition of the catalytic activity of Malt1 in T cells results in their inability to activate mTORC1-dependent signaling pathways in response to stimulation via the TCR plus CD28 but not by other activation pathways. The activation of mTORC1 is impaired after inhibition of the kinase PKC, which activates the Carma1-Malt1 complex. Inhibition or loss of Malt1 or Carma1 also blunts T cell proliferation and the metabolic switch from oxidative phosphorylation to glycolysis in response to TCR stimulation. Thus, a PKC-Carma1-Malt1–dependent pathway is required for the activation of mTORC1 in response to signaling via the TCR.

Sci. Signal. (10 June 2014) doi:10.1126/scisignal.2005169