First published April 1, 2004 - More info
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.
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
Original citation: J. Clin. Invest.112:286–297 (2003). doi:10.1172/JCI18025.
Citation for this corrigendum: J. Clin. Invest.113:1069 (2004). doi:10.1172/JCI18025E1.
The legends for Figures 6 and 7 contained inaccuracies, and the correct versions appear below. The conclusions of the article are unaffected.
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 (black bars) or presence (white 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.
Altered expression of BAFF-Rs and CD40 on activated human B cells. CFSE-labeled memory B cells were cultured as in Figure 3a. Cells were harvested and incubated with anti-CD38 mAb in combination with (a) soluble BAFF or mAb specific for (b) BAFF-R, (c) TACI, (d) BCMA, or (e) CD40. Expression of these receptors on B cells in populations 1 (left panel), 2 (middle panel), and 3 (right panel) was determined. For each plot, the thick and thin lines represent the fluorescence of cells incubated with the specific or isotype control mAb or protein, respectively. These results are representative of three independent experiments.