NF-kappaB activation pathways induced by T cell costimulation.

Analysis of knockout mice and of T cells deficient for individual signaling proteins allowed the identification of novel members of the costimulation-induced NF-kappaB activation pathway while biochemical approaches started to unveil their functional mechanisms. These results show that NF-kappaB activation depends on an early wave of tyrosine phosphorylation that allows the inducible formation of multiprotein complexes containing several proteins required for NF-kappaB activation: adaptor proteins including Src homology 2 domain-containing leukocyte phosphoprotein 76 (SLP-76) and proteins with enzymatic activity, such as phospholipase C (PLC) gamma and the exchange factor Vav1. While Vav1 contributes to Rac-dependent reorganization of the actin cytoskeleton, activated PLCgamma1 generates the protein kinase C (PKC) activator diacylglycerol. In T cells, the novel PKC isoform PKCtheta is indispensable for NF-kappaB activation and its enzymatic activity depends on recruitment to the immunological synapse. Downstream from PKCtheta, the caspase recruitment domain (CARD) proteins CARD11/CARMA1 and Bcl10 relay T cell receptor-derived signals to the IkappaB kinase (IKK) complex. Many members of the NF-kappaB activation cascade, including the IKKs, are either constitutively or inducibly translocated to the lipid raft fraction, showing a highly organized spatial distribution of these NF-kappaB activating proteins.