Insights into the role of C3d dimers in B cell activation and Staphylococcal immune evasion

Cleavage of C3 to C3a and C3b plays a central role in the generation of complement-mediated defences. Although the thioester-mediated surface deposition of C3b has been well-studied, fluid-phase dimers of C3 fragments remain largely unexplored. Here we present the first X-ray crystal structures of disulphide-linked human C3d dimers and show they undergo structurally-stabilising N-terminal domain swapping when in complex with the Staphylococcus aureus immunomodulator Sbi. Through binding studies and flow cytometric analyses we uncover the physiologically-relevant roles of these dimers in crosslinking complement receptor 2 and modulating B cell activation to potentially promote anergy. This potential induction of cellular tolerance by C3d dimers could contribute to Sbi-mediated S. aureus immune evasion as well as limit autoreactive immune responses under physiological conditions. Thus, insights gained from our findings could inform the design of novel therapies for autoimmune disorders and enhance our understanding surrounding the importance of complement in the fluid phase.