CD40 signaling regulates both adaptive and innate immune receptors through TRAF degradation (84.3)

Abstract

Abstract CD40, a tumor necrosis family member, is a costimulatory molecule central to adaptive immune responses. CD40 activates many of the same pathways as innate immune receptors; however, the outcome of CD40 signaling is much different. Whereas innate immune receptors rapidly initiate early protective immune responses, CD40 engagement and signaling results in a fundamental change toward a regulated, adaptive immune response. The specific regulatory signals that restrain the CD40 response have remained elusive. Here we show that upon signaling, CD40 specifically negatively regulates its own signals as well as those delivered by other receptors that rely on TRAF2 and TRAF3 for signaling. This negative regulation of CD40 and TLR signals is caused by CD40’s unique ability to induce both TRAF2 and TRAF3 degradation upon signaling. Hence CD40, as a molecule central to immune responses, is not only able to regulate its own signals, it is able to transition an immune response from an early inflammatory stage to a regulated adaptive stage.