RESUMO
Re-exposure to an antigen generates abundant antibody responses and drives the formation of secondary germinal centers (GCs). Recall GCs in mice consist almost entirely of naïve B cells, whereas recall antibodies derive overwhelmingly from memory B cells. Here, we examine this division between cellular and serum compartments. After repeated immunization with the same antigen, tetramer analyses of recall GCs revealed a marked decrease in the ability of B cells in these structures to bind the antigen. Boosting with viral variant proteins restored antigen binding in recall GCs, as did genetic ablation of primary-derived antibody-secreting cells through conditional deletion of Prdm1, demonstrating suppression of GC recall responses by pre-existing antibodies. In hapten-carrier experiments in which B and T cell specificities were uncoupled, memory T cell help allowed B cells with undetectable antigen binding to access GCs. Thus, antibody-mediated feedback steers recall GC B cells away from previously targeted epitopes and enables specific targeting of variant epitopes, with implications for vaccination protocols.
Assuntos
Linfócitos B , Centro Germinativo , Memória Imunológica , Centro Germinativo/imunologia , Animais , Camundongos , Memória Imunológica/imunologia , Linfócitos B/imunologia , Células T de Memória/imunologia , Camundongos Endogâmicos C57BL , Fator 1 de Ligação ao Domínio I Regulador Positivo/imunologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Formação de Anticorpos/imunologia , Células B de Memória/imunologia , Camundongos KnockoutRESUMO
Re-exposure to an antigen generates serum antibody responses that greatly exceed in magnitude those elicited by primary antigen encounter, while simultaneously driving the formation of recall germinal centers (GCs). Although recall GCs in mice are composed almost entirely of naïve B cells, recall antibody titers derive overwhelmingly from memory B cells, suggesting a division between cellular and serum compartments. Here, we show that this schism is at least partly explained by a marked decrease in the ability of recall GC B cells to detectably bind antigen. Variant priming and plasmablast ablation experiments show that this decrease is largely due to suppression by pre-existing antibody, whereas hapten-carrier experiments reveal a role for memory T cell help in allowing B cells with undetectable antigen binding to access GCs. We propose a model in which antibody-mediated feedback steers recall GC B cells away from previously targeted epitopes, thus enabling specific targeting of variant epitopes.