Generation of independent complement receptor 1 and complement receptor 2 knockout mice and defining the role of complement receptor 1 in humoral immunity

Complement receptor (Cr)1 and Cr2 have long been studied in relation to humoral immunity. These receptors are alternative splice variants of the murine Cr2 gene, and all previous investigations of the effect of Cr1 and Cr2 on humoral immunity have been conducted utilizing mouse models deficient in both Cr1 and Cr2. To date, very little effort has been taken to delineate the functional roles of each receptor. The known molecular differences and independent transcription of Cr1 and Cr2 suggest a functional significance for each of these that should not be ignored. Additionally, I discovered that Cr1 and Cr2 are differentially expressed by follicular dendritic cells (FDCs) and B cells. It is shown here that B cells predominantly express Cr2, while Cr1 is the near exclusive Cr2 product on FDCs. To investigate the independent roles of Cr1 and Cr2 in the context of an immune response, I generated two new mouse strains: Cr1KO and Cr2KO. The predominance of Cr1 on FDCs led to the hypothesis that Cr1 primarily functions in FDC promotion of germinal center (GC) reactions, which is likely mediated by the known complement-dependent deposition of immune complexes in follicles. Analysis of these new strains demonstrated that Cr1 and Cr2 have marked differences in their function in humoral immunity. In many cases, the B cell responses which are decreased in the Cr1/2- deficient mouse are unaffected in the Cr1-deficient mouse. It is shown that Cr1- deficiency on FDCs results in a significant reduction in the maintenance of GC B cells and memory B cell production. Intriguingly, classically GC-independent responses, such as antigen-specific IgM and IgM memory B cells, are also reduced. However, B cell responses that cannot proceed through germinal centers, notably T-independent B cell responses, are not affected by Cr1-deficiency. In total, this work defines the Cr1KO and Cr2KO mouse lines as new models for the study of Cr1 and Cr2 in humoral immunity. In addition to its use in the study of the function of Cr1, the Cr1KO mouse is an invaluable tool in the investigation of GC biology.