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.:|
|Publisher Name||JOURNAL OF EXPERIMENTAL MEDICINE|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20048285|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/10255|