Antigen-independent signalosome of CARMA1, PKCθ, and TNF receptor-associated factor 2 (TRAF2) determines NF-κB signaling in T cells

NF-kappa B activation is essential for T-cell responses, and costimulatory molecules in the TNF receptor (TNFR) superfamily are viewed as a major source of this signal. Although the TNFR family recruits TNFR-associated factor (TRAF) molecules leading to IKK alpha/beta/gamma activation, it is not clear whether simple binding of TRAFs explains why they are such strong activators of NF-kappa B and so important for T-cell immunity. We now show that one TNFR family member, OX40 (CD134), after ligation by OX40L, assembles a unique complex that not only contains TRAF2, RIP, and IKK alpha/beta/gamma but also CARMA1, MALT1, BCL10, and PKC theta, molecules previously shown to regulate NF-kappa B activation through the T-cell receptor (TCR). The OX40 signalosome is formed in membrane microdomains irrespective of TCR engagement, and strongly promotes NF-kappa B activation only if CARMA1 and PKC theta are recruited. This NF-kappa B signal allows effector/memory T cells to survive when antigen is no longer available. Thus, by recruiting TCR-related intracellular molecules into the TRAF2 complex, OX40 provides the T cell with a high level of NF-kappa B activity needed for longevity.