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

Danielle T. Avery, Elissa K. Deenick, Cindy S., Santi Suryani, Nicholas Simpson, Gary Y. Chew, Tyani D. Chan, Umamainthan Palendira, Jacinta Bustamante, Stéphanie Boisson-Dupuis, Sharon Choo, Karl E. Bleasel, Jane Peake, Cecile King, Martyn A. French, Dan Engelhard, Sami Al-Hajjar, Saleh Al-Muhsen, Klaus Magdorf, Joachim Roesler, Peter D. Arkwright, Pravin Hissaria, D. Sean Riminton, Melanie Wong, Robert Brink, David A. Fulcher, Jean-Laurent Casanova, Matthew C. Cook, Stuart G. Tangye

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.