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* Immunology Program, Garvan Institute of Medical Research, Darlinghurst, Australia; and
St. Vincent’s Clinical School, University of New South Wales, Sydney, New South Wales, Australia
To optimize the initial wave of Ab production against T-dependent Ags, primary B cell clones with the highest Ag 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 Ag-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 6 days of a T-dependent B cell response and to identify the steps at which initial Ag affinity has a major impact. Ag-specific B cells proliferated within splenic follicles from days 1.0 to 3.0 before undergoing a dynamic phase of multilineage differentiation (days 3.0–4.0) that generated switched and unswitched populations of germinal center B cells, early memory B cells, and extrafollicular PBs. PB differentiation was marked by synchronous up-regulation of CXCR4 and down-regulation of CXCR5 and the adoption of a unique BCRhigh phenotype by unswitched PBs. Differences in Ag 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, and interacted directly with Ag-specific extrafollicular Th cells, suggesting that IL-21-independent T cell help may drive extrafollicular PB expansion in responses to foreign Ag.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Program Grant 427620 from the National Health and Medical Research Council of Australia. R.B. was supported by a Senior Research Fellowship, and D.G. by a Biomedical Research Fellowship from the National Health and Medical Research Council of Australia.
2 Address correspondence and reprint requests to Dr. Robert Brink, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst NSW 2010, Australia. E-mail address: r.brink{at}garvan.org.au
3 Abbreviations used in this paper: TD, T dependent; GC, germinal center; HEL, hen egg lysozyme; PALS, periarteriolar lymphoid sheath; PB, plasmablast; PC, plasma cell; TFH, Th follicular.
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