Avery, Danielle TDeenick, ElissaMa, CindySuryani, SantiSimpson, NickChew, GaryChan, TyaniPalendira, UmamainthanBustamante, JacintaBoisson-Dupuis, StephanieChoo, SharonBleasel, Karl E.Cook, MatthewArkwright, Peter D2015-12-070022-1007http://hdl.handle.net/1885/25186Engagement 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.Keywords: immunoglobulin; interleukin 21; interleukin 21 receptor; STAT1 protein; STAT3 protein; antibody response; antigen specificity; article; B lymphocyte; B lymphocyte differentiation; controlled study; effector cell; gene inactivation; gene mutation; human; h201010.1084/jem.200917062016-06-14