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.


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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