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

E.K.K. Deenick, D.T. Avery, L.J. Berglund, M.L. Ives, L. Moens, J.L. Stoddard, J. Bustamante, S. Boisson-Dupuis, M. Tsumura, M. Kobayashi, P.D. Arkwright, D. Averbuch, D. Engelhard, J.R. Roesler, J.E. Peake, M. Wong, S. Adelstein, S. Choo, J.M. Smart, Martyn FrenchD.A. Fulcher, M. Cook, C. Pïcard, A.H. Durandy, C. Klein, S.M. Holland, G.D.C. Uzel, J.L. Casanova., C.S. Ma, S.G. Tangye, A. Chan

    Research output: Contribution to journalArticle

    97 Citations (Scopus)

    Abstract

    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. © 2013 Deenick et al.
    Original languageEnglish
    Pages (from-to)2739-2753
    JournalJournal of Experimental Medicine
    Volume210
    Issue number12
    DOIs
    Publication statusPublished - 2013

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