Follicular dendritic cells and complement receptors 1 and 2 are important for the generation of humoral immunity. Cr1/2 expression on B cells and FDC has been shown to provide a secondary signal for B cell activation, to facilitate transport of antigen in immune follicles, and to enhance retention of immune complexes by FDC. We show here that murine B cells predominantly express the Cr2 product from the Cr2 gene while FDC nearly exclusively express the Cr1 isoform generated from the Cr2 gene. To define the specific role of Cr1, we have 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 naïve serum antibodies but altered levels of natural antibodies. Immunization of the Cr1KO animal demonstrates deficient antibody responses to T-dependent but not T-independent antigens. Germinal centers from the immunized Cr1KO animal possess a deficiency in activated B cells, similar to that seen for the animal lacking both Cr1 and Cr2, or C3. Finally, animals lacking only Cr1 respond similar to the WT animal to infections with Streptococcus pneumoniae, a pathogen that animals lacking C3 or both Cr1 and Cr2 are particularly sensitive to. These data, in total, suggest that the production of Cr1 primarily by FDC is critical in the generation of appropriately activated B cells of the germinal center and the generation of mature antibody responses.

Rapid identification of antigens during a primary immune response requires timely detection, opsonization, and delivery to immune follicles for B cell activation. Evidence demonstrates complement sequestration of antigen is important for efficient detection and antibody production by B cells. Follicular dendritic cells (FDC), which promote B cell activation and maturation by organizing germinal centers and retaining antigen, as well as B cells, are exclusive expressers of the Complement Receptor 2 (Cr2) gene products Cr1 and Cr2. We show here that Cr1 is the nearly exclusive product of the Cr2 gene on FDC and, in contrast, Cr2 is the predominant product on B cells. Consistent with FDC restricted expression of Cr1, immunization of Cr1 deficient (Cr1KO) mice demonstrated deficiencies in antibody and B cell responses to T-dependent but not T-independent (TI) antigens. Cr1KO mice exhibit a reduction in antigen specific IgM and IgG3 during primary immunization with TNP-KLH, and do not generate activated germinal center B cells as readily as wildtype mice in response to sheep red blood cell. Cr1KO mice generate effective immunity to Streptococcus pneumoniae, which typically is controlled by TI induced antibody against the bacterial polysaccharide capsule. In total the results of this study define a specific role for Cr1 in B cell germinal center maturation, and defines the Cr1KO mouse as a new tool for studying activation of B cells during primary immune responses.

Complement receptors (Cr)1 and 2 have been established to have important roles in control of complement activation in the immune microenvironment and B cell responses. Previous work investigating the effects of these receptors in vivo has relied on a double knockout mouse line in which each of these receptors was deleted. However, two drawbacks of this mouse must be acknowledged: 1) that both receptors are deleted and roles of each must be inferred, and 2) that the essential B cell signaling protein CD19 is expressed at a significantly higher level than WT cells. We have created a Cr1 deficient line of mice (expressing Cr2) by homologous gene targeting that expresses normal levels of Cr2 gene products on B cells. This animal has normal ratios of bone marrow, B2 cell, and B1 B cell populations. Cr2 negative marrow B cells express the same amount of surface CD19 as WT but mature Cr2-expressing B cells express less. These Cr2-only mice generate normal to slightly enhanced antibody titers to T-dependent and T-independent (both 1 and 2 antigens.) In conclusion Cr1 is not critical for development and maintenance of B cell populations nor for the generation of antibodies to naïve antigens. This mouse, along with the Cr1/2KO, will be a critical tool in delineating Cr1 specific immune response effects.