Optimal Germinal Center B Cell Activation

Follicular dendritic cells (FDCs) and complement receptor (Cr)1 and complement receptor (Cr)2 are important for the generation of humoral immunity. Cr1/2 expression on B cells and FDCs was shown to provide a secondary signal for B cell activation, to facilitate transport of Ag in immune follicles, and to enhance retention of immune complexes by FDCs. We show in this study that murine B cells predominantly express the Cr2 product from the Cr2 gene, whereas FDCs almost exclusively express the Cr1 isoform generated from the Cr2 gene. To define the specific role of Cr1, we created an animal that maintains normal cell-restricted expression of Cr2 but does not express Cr1. Cr1-deficient (Cr1KO) mice develop normal B1 and B2 immature and mature B cell subsets and have normal levels of naive serum Abs but altered levels of natural Abs. Immunization of the Cr1KO animal demonstrates deficient Ab responses to T-dependent, but not T-independent, Ags. Germinal centers from the immunized Cr1KO animal possess a deficiency in activated B cells, similar to that seen for animals lacking both Cr1 and Cr2 or C3. Finally, animals lacking only Cr1 respond similarly to wild-type animals to infections with Streptococcus pneumoniae, a pathogen to which animals lacking C3 or both Cr1 and Cr2 are particularly sensitive. Altogether, these data suggest that the production of Cr1, primarily by FDCs, is critical in the generation of appropriately activated B cells of the germinal center and the generation of mature Ab responses. A ntibodies (Igs) are the major effectors of the adaptive immune response, and different isotype classes of Ab are produced to achieve different effects with Ab of the same specificity. Ig class-switch recombination is a hallmark of B cell responses to T-dependent (TD) Ags (1). These reactions occur within immune follicles of secondary immune structures, such as the spleen and lymph nodes (2). Central to follicles are follicular den-dritic cells (FDCs), which establish the zonal identity (3) and act as a concentrated depot of Ag. In the course of an immune challenge, Ag is trafficked to the FDCs (4–6), where follicular B cells are recruited for surveillance of retained Ag. BCR specificity for an Ag retained on an FDC results in internalization and processing for presentation to T cells. The B cell then migrates to the T cell zone and presents the processed peptide to Th cells in the context of class II MHC. Upon a secondary signal …