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Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells

2013; Rockefeller University Press; Volume: 210; Issue: 12 Linguagem: Inglês

10.1084/jem.20130323

1540-9538

Elissa K. Deenick, Danielle T. Avery, Anna Chan, Lucinda J. Berglund, Megan L. Ives, Leen Moens, Jennifer Stoddard, Jacinta Bustamante, Stéphanie Boisson‐Dupuis, Miyuki Tsumura, Masao Kobayashi, Peter D. Arkwright, Diana Averbuch, Dan Engelhard, Joachim Roesler, Jane Peake, Melanie Wong, Stephen Adelstein, Sharon Choo, Joanne Smart, Martyn A. French, David A. Fulcher, Matthew Cook, Capucine Pïcard, Anne Durandy, Christoph Klein, Steven M. Holland, Gülbû Uzel, Jean‐Laurent Casanova, S. Cindy, Stuart G. Tangye,

Immune Cell Function and Interaction

Long-lived antibody memory is mediated by the combined effects of long-lived plasma cells (PCs) and memory B cells generated in response to T cell-dependent antigens (Ags). IL-10 and IL-21 can activate multiple signaling pathways, including STAT1, STAT3, and STAT5; ERK; PI3K/Akt, and potently promote human B cell differentiation. We previously showed that loss-of-function mutations in STAT3, but not STAT1, abrogate IL-10- and IL-21-mediated differentiation of human naive B cells into plasmablasts. We report here that, in contrast to naive B cells, STAT3-deficient memory B cells responded to these STAT3-activating cytokines, differentiating into plasmablasts and secreting high levels of IgM, IgG, and IgA, as well as Ag-specific IgG. This was associated with the induction of the molecular machinery necessary for PC formation. Mutations in IL21R, however, abolished IL-21-induced responses of both naive and memory human B cells and compromised memory B cell formation in vivo. These findings reveal a key role for IL-21R/STAT3 signaling in regulating human B cell function. Furthermore, our results indicate that the threshold of STAT3 activation required for differentiation is lower in memory compared with naive B cells, thereby identifying an intrinsic difference in the mechanism underlying differentiation of naive versus memory B cells.