Anti-BCL10 (aa 1-233) polyclonal antibody

Antigen primed T lymphocytes need to expand and persist to promote adaptive immunity. The growth and survival signals that control this are in large part provided by the NE-kappa B pathway in activated or effector/memory T cells. Although several membrane receptors impact NE-kappa B activation, signaling from OX40 (CD134, TNFRSF4), a member of the tumor necrosis factor receptor (TNFR) superfamily, has proven to be important for T cell immunity and a strong contributor to NE-kappa B activity. PKC theta directs the T cell receptor (TCR) and CD28-dependent assembly of a CBM complex (CARMA1, BCL10, and MALT1) for efficient activation of NE-kappa B, raising the question of whether other membrane bound receptors that activate NE-kappa B also require this PKC theta-CBM axis to control TCR-independent T cell activity. We discuss here our recent data demonstrating that after ligation by OX40L (CD252, TNFSF4) expressed on antigen-presenting cells, OX40 translocates into detergent-insoluble membrane lipid microdomains (DIM or lipid rafts) in T cells irrespective of TCR signals, and assembles into a signaling complex containing PKC theta, together with TRAF2, RIP 1, the CBM complex, and the IKK alpha/beta/gamma complex. PKC theta is required for optimal NE-kappa B activation mediated by OX40 and thus works as an essential component of this OX40 signalosome. We also discuss the likelihood that other TNFR superfamily molecules might complex with PKC theta in T cells, and whether PKC isoforms may be critical to the function of TNFR molecules in general.

Triggering of antigen receptors on lymphocytes is critical for initiating adaptive immune response against pathogens. T-cell receptor (TCR) engagement induces the formation of the Carma1-Bcl10-Malt1 (CBM) complex that is essential for activation of the IkB kinase (IKK)/NF-kappa B pathway. However, the molecular mechanisms that link CBM complex formation to IKK activation remain unclear. Here we report that Malt1 is polyubiquitinated upon T-cell activation. Ubiquitin chains on Malt1 provide a docking surface for the recruitment of the IKK regulatory subunit NEMO/IKK gamma. TRAF6 associates with Malt1 in response to T-cell activation and can function as an E3 ligase for Malt1 in vitro and in vivo, mediating lysine 63-linked ubiquitination of Malt1. Multiple lysine residues in the C-terminus of Malt1 serve as acceptor sites for the assembly of polyubiquitin chains. Malt1 mutants that lack C-terminal ubiquitin acceptor lysines are impaired in rescuing NF-kappa B signaling and IL-2 production in Malt1-/- T cells. Thus, our data demonstrate that induced Malt1 ubiquitination is critical for the engagement of CBM and IKK complexes, thereby directing TCR signals to the canonical NF-kappa B pathway.