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B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans


Engagement of cytokine receptors by specific ligands activate Janus kinase-signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21-induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients.

ISBN 1540-9538 (Linking) 1540-9538 (Linking)
Authors Avery, D. T.; Deenick, E. K.; Ma, C. S.; Suryani, S.; Simpson, N.; Chew, G. Y.; Chan, T. D.; Palendira, U.; Bustamante, J.; Boisson-Dupuis, S.; Choo, S.; Bleasel, K. E.; Peake, J.; King, C.; French, M. A.; Engelhard, D.; Al-Hajjar, S.; Al-Muhsen, S.; Magdorf, K.; Roesler, J.; Arkwright, P. D.; Hissaria, P.; Riminton, D. S.; Wong, M.; Brink, R.; Fulcher, D. A.; Casanova, J. L.; Cook, M. C.; Tangye, S. G.:
Published Date 2010-01-18
Published Volume 207
Published Issue 1
Published Pages 155-71
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version