B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans
Date
2010
Authors
Avery, Danielle T
Deenick, Elissa
Ma, Cindy
Suryani, Santi
Simpson, Nick
Chew, Gary
Chan, Tyani
Palendira, Umamainthan
Bustamante, Jacinta
Boisson-Dupuis, Stephanie
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Rockefeller University Press
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.
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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; h
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Journal of Experimental Medicine
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Journal article
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2037-12-31
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