Authors
Danielle T. Avery, Garvan Institute of Medical Research
Elissa K. Deenick, University of New South Wales
Cindy S. Ma, University of New South Wales
Santi Suryani, University of New South Wales
Nicholas Simpson, Australian National University
Gary Y. J Chew, Australian National UniversityFollow
Tyani D. Chan, University of New South Wales
Umamainthan Palendira, University of New South Wales
Jacinta Bustamante, University Paris Descartes
Stéphanie Boisson-Dupuis, University Paris Descartes
Sharon Choo, Royal Children's Hospital Melbourne
Karl E. Bleasel, Royal Melbourne Hospital
Jane Peake, Royal Children's Hospital Brisbane
Cecile King, University of New South Wales
Martyn French, Royal Perth Hospital, WA
Dan Engelhard, Hadassah University Hospital
Sami Al-Hajjar, King Faisal Specialist Hospital And Research Centre
Saleh Al-Muhsen, King Faisal Specialist Hospital And Research Centre
Klaus Magdorf, Humboldt University Berlin
Joachim Roesler, University Clinic Carl Gustav Carus
Peter D. Arkwright, University of Manchester
Pravin Hissaria, Royal Adelaide Hospital, SA
D. Sean Riminton, Concord Hospital
Melanie Wong, Westmead Hospital
Robert Brink, University of New South Wales
David A. Fulcher, Westmead Hospital
Jean-Laurent Casanova, University Paris Descartes
Matthew C. Cook, Australian National University
Stuart Tangye, University of Technology Sydney
Abstract
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.
Publication Details
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., Wong, M., Brink, R., Fulcher, D. A., Casanova, J., Cook, M. C. & Tangye, S. G. (2010). B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans. Journal of Experimental Medicine, 207 (1), 156-171.