BAFF selectively enhances the survival of plasmablasts generated from human memory B cells
Danielle T. Avery, Susan L. Kalled, Julia I. Ellyard, Christine Ambrose, Sarah A. Bixler, Marilyn Thien, Robert Brink, Fabienne Mackay, Philip D. Hodgkin, Stuart G. Tangye
Danielle T. Avery, Susan L. Kalled, Julia I. Ellyard, Christine Ambrose, Sarah A. Bixler, Marilyn Thien, Robert Brink, Fabienne Mackay, Philip D. Hodgkin, Stuart G. Tangye
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Article Immunology

BAFF selectively enhances the survival of plasmablasts generated from human memory B cells

Abstract

The generation of Ig-secreting cells (ISCs) from memory B cells requires interactions between antigen-specific (Ag-specific) B cells, T cells, and dendritic cells. This process must be strictly regulated to ensure sufficient humoral immunity while avoiding production of pathogenic autoantibodies. BAFF, a member of the TNF family, is a key regulator of B cell homeostasis. BAFF exerts its effect by binding to three receptors — transmembrane activator of and CAML interactor (TACI), B cell maturation antigen (BCMA), and BAFF receptor (BAFF-R). To elucidate the contribution of BAFF to the differentiation of B cells into ISCs, we tracked the fate of human memory B cells stimulated with BAFF or CD40L. BAFF and CD40L significantly increased the overall number of surviving B cells. This was achieved via distinct mechanisms. CD40L induced proliferation of nondifferentiated blasts, while BAFF prevented apoptosis of ISCs without enhancing proliferation. The altered responsiveness of activated memory B cells to CD40L and BAFF correlated with changes in surface phenotype such that expression of CD40 and BAFF-R were reduced on ISCs while BCMA was induced. These results suggest BAFF may enhance humoral immunity in vivo by promoting survival of ISCs via a BCMA-dependent mechanism. These findings have wide-ranging implications for the treatment of human immunodeficiencies as well as autoimmune diseases.

Authors

Danielle T. Avery, Susan L. Kalled, Julia I. Ellyard, Christine Ambrose, Sarah A. Bixler, Marilyn Thien, Robert Brink, Fabienne Mackay, Philip D. Hodgkin, Stuart G. Tangye

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BAFF increases the generation of ISC from activated memory B cells. (a a...
BAFF increases the generation of ISC from activated memory B cells. (a and b) Memory B cells were preactivated with CD40L and IL-2/IL-10 for 4 days and then recultured with (a) media (black bars), or (b) IL-2/IL-10 alone (black bars) or in the presence of CD40L (white bars) or BAFF (gray bars). Each value represents the mean Ig secretion ± SEM of five (a) or seven (b) experiments using cells from different donors. *P < 0.05; **P < 0.01. (c) Secondary B cell cultures were performed in the absence (white bars) or presence (black bars) of soluble TACI-Ig (20 μg/ml). The values represent the mean IgA ± SD of duplicate samples. (d) Memory B cells were preactivated with CD40L/IL-2/IL-10 for 4 days and then recultured with IL-2/IL-10 alone or in the presence of BAFF. The total number of cells secreting IgM (black bars), IgG (white bars), and IgA (gray bars) was determined by ELISPOT. Expt, experiment. (e) IgM+ and (f) IgG/A/E+ memory B cells were isolated by cell sorting, and the amount of IgA secreted during secondary culture with IL-2/IL-10 (black bars), CD40L/IL-2/IL-10 (white bars), or BAFF/IL-2/IL-10 (gray bars) was determined. The scales of the y axes of these graphs are different to enable meaningful comparison. (g) Cells corresponding to populations 2 and 3 were isolated by sorting, recultured with IL-2/IL-10 (black bars), CD40L/IL-2/IL-10 (white bars), or BAFF/IL-2/IL-10 (gray bars), and the amount of IgA secreted was then determined.