BAFF selectively enhances the survival of plasmablasts generated from human memory B cells
Danielle T. Avery, … , Philip D. Hodgkin, Stuart G. Tangye
Danielle T. Avery, … , Philip D. Hodgkin, Stuart G. Tangye
Published July 15, 2003
Citation Information: J Clin Invest. 2003;112(2):286-297. https://doi.org/10.1172/JCI18025.
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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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Figure 5

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CD40L and BAFF have distinct effects on proliferation and survival of CD...
CD40L and BAFF have distinct effects on proliferation and survival of CD38– and CD38+ B cells. CFSE-labeled memory B cells were cultured as described in Figure 3a. The percentage of (a) CD38– and (b) CD38+ B cells present in different divisions after primary culture (day 4; thick line, squares) or following secondary culture with IL-2/IL-10 (diamonds), CD40L and IL-2/IL-10 (circles), or BAFF and IL-2/IL-10 (triangles) was determined by division slicing. Each value represents the mean ± SEM of five different experiments. (c) Ramos B cells were cultured overnight in the absence of serum. Expression of active caspase-3 by total cells (thin line), live cells (dotted line), and dead cells (bold line) was then determined by intracellular staining and flow cytometry using gates established according to forward- and side-scatter characteristics. (d) The percentage of populations 2 and 3 B cells expressing active caspase-3 following secondary culture with IL-2/IL-10 (black bars), CD40L and IL-2/IL-10 (white bars), or BAFF and IL-2/IL-10 (gray bars) was determined as described for c by gating on both live and dead cells. Each value represents the mean ± SEM of three different experiments. **P < 0.01.