Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells
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.
|Authors||Deenick, E. K.; Avery, D. T.; Chan, A.; Berglund, L. J.; Ives, M. L.; Moens, L.; Stoddard, J. L.; Bustamante, J.; Boisson-Dupuis, S.; Tsumura, M.; Kobayashi, M.; Arkwright, P. D.; Averbuch, D.; Engelhard, D.; Roesler, J.; Peake, J.; Wong, M.; Adelstein, S.; Choo, S.; Smart, J. M.; French, M. A.; Fulcher, D. A.; Cook, M. C.; Picard, C.; Durandy, A.; Klein, C.; Holland, S. M.; Uzel, G.; Casanova, J. L.; Ma, C. S.; Tangye, S. G.;|
|Publisher Name||JOURNAL OF EXPERIMENTAL MEDICINE|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/24218138|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/11731|