Protein Kinase C-δ Negatively Regulates T Cell Receptor-induced NF-κB Activation by Inhibiting the Assembly of CARMA1 Signalosome

T-cell receptor (TCR)-induced T-cell activation is a critical event in adaptive immune responses. The engagement of TCR complex by antigen along with the activation of the costimulatory receptors trigger a cascade of intracellular signaling, in which caspase recruitment domain-containing membrane-associated guanylate kinase 1 (CARMA1) is a crucial scaffold protein. Upon stimulation, CARMA1 recruits downstream molecules including B-cell CLL/lymphoma 10 (Bcl10), mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1), and TRAF6 to assemble a specific TCR-induced signalosome that triggers NF-kappa B and JNK activation. In this report, we identified protein kinase C delta (PKC delta) as a CARMA1-associated protein by a biochemical affinity purification approach. PKC delta interacted with CARMA1 in TCR stimulation-dependent manner in Jurkat T cells. Overexpression of PKC delta inhibited CARMA1-mediated NF-kappa B activation, whereas knockdown of PKC delta potentiated TCR-triggered NF-kappa B activation and IL-2 secretion in Jurkat T cells. Reconstitution experiments with PKC delta kinase-dead mutant indicated that the kinase activity of PKC delta was dispensable for its ability to inhibit TCR-triggered NF-kappa B activation. Furthermore, we found that PKC delta inhibited the interaction between MALT1 and TRAF6, but not the association of CARMA1 with PKC theta, Bcl10, or MALT1. These observations suggest that PKC delta is a negative regulator in T cell activation through inhibiting the assembly of CARMA1 signalosome.