Regulation of humoral immune responses by CD21/CD35

Before antigen-specific immunity arises, the complement system responds by activation through the classical and/or alternative pathways leading to the covalent deposition of complement fragments. Three models, not mutually exclusive, have been proposed to explain how these complement fragments interact with their receptors, CD21/CD35, to enhance humoral immune responses: i) CD21/CD35 retain and focus antigens for optimal presentation; ii) CD21/CD35 on B cells serve as enhancing co-receptors for B-cell antigen receptor (BCR) signaling; iii) CD21/CD35 regulate B-cell responses, by CD19 aggregation. The coreceptor model led us to predict that CD21/CD3 5 may lower the threshold of BCR affinity to diversify the repertoire of humoral immune responses, but surprisingly, CD21/CD3 5-deficient mice expressing a transgenic BCR with very low affinity (Kalpha approximately =1.2 x 10(5) M(-1)) for the (4-hydroxy-3-nitrophenyl)acetyl hapten generated significant antibody and germinal center responses to even low doses of antigens in alum. The magnitudes of these responses were much below those of normal controls but higher doses of antigens substantially rectified these deficits. Thus, while CD21/CD35 play important roles in humoral immunity, our observations provide little support to the hypothesis that CD21/CD35 promote clonal diversity in immune responses by helping recruit low-affinity B cells.