Abstract
The CD21/35 proteins are complement receptors expressed on B cells and follicular dendritic cells (FDCs) which places them squarely within the realm of controlling and interpreting activation states of the innate immune response. Both proteins are composed of extracellular short consensus repeats that bind to C3 breakdown products; C3d,g and C3b, C4b, respectively. Previous studies analyzing mice deficient in the Cr2 gene have identified the main function for CD21 as a member of the B cell co-receptor complex. The longer protein, CD35, functions as a co-factor for the cleavage of activated C3b and C4b on antigens and immune complexes into their inactive forms. Such regulation of complement at the level of convertase inhibition is necessary to prevent unintentional inflammation and host cell damage within tissues. However, the importance for CD35 as a complement regulatory protein on B cells and FDCs within the spleen has been largely overlooked. Our analysis of gene expression profiles of resting wild type (WT) and CD21/35 deficient animals indicates the enhanced expression of a wide range of inflammatory mediators from CD11b+ cells in the absence of CD21/35 on B cells and FDCs. Splenic cell population analysis revealed a higher percentage of GR1lo/CD31+ immature myeloid cells as well as an increase in immature neutrophils within the CD21/35 deficient spleen. Finally, dis-regulated complement activation is implicated in the altered gene expression as depletion of C3 or inhibition of C3a receptor signaling returned inflammatory gene expression within the spleen to WT levels. These data suggest that the overall environment of the CD21/35−/− spleen is quite different from that of the WT animal not only during B cell activation, but at the level of complement activation. These differences may directly impact phenotypes previously associated with the B-cell co-receptor function of CD21and better highlight the role for CD35 as a complement regulatory protein.