Publications

Abstract

To optimize the initial wave of antibody production against T-dependent antigens, primary B cell clones with the highest antigen affinity are selected to generate the largest extrafollicular plasmablast (PB) responses. The mechanism behind this remains undefined, primarily due to the difficulty of analyzing low-frequency antigen-specific B cells during the earliest phases of the immune response when key differentiation decisions are made. In this study, a high resolution in vivo mouse model was used to characterize in detail the first six days of a T-dependent B cell response and to identify the steps at which initial antigen affinity has a major impact. Antigen-specific B cells proliferated within splenic follicles from days 1.0-3.0 before undergoing a dynamic phase of multi-lineage differentiation (days 3.0-4.0) that generated switched and unswitched populations of germinal center (GC) B cells, early memory B cells, and extrafollicular PBs. PB differentiation was marked by synchronous upregulation of CXCR4 and downregulation of CXCR5 and the adoption of a unique BCRhi phenotype by unswitched PBs. Differences in antigen affinity of >50-fold did not markedly affect the early stages of the response, including the differentiation and extrafollicular migration of PBs. However, high affinity PBs underwent significantly greater expansion within the splenic bridging channels and red pulp, due to both increased proliferation and decreased apoptosis. Extrafollicular PBs maintained class II MHC but not IL 21R expression, leaving open the possibility that interactions with extrafollicular TH cells drive PB expansion but arguing against direct involvement of IL-21.