IL-21 signalling via STAT3 primes human naive B cells to respond to IL-2 to enhance their differentiation into plasmablasts
B-cell responses are guided by the integration of signals through the BCR, CD40 and cytokine receptors. The common gamma chain (gammac)-binding cytokine IL-21 drives humoral immune responses via STAT3-dependent induction of transcription factors required for plasma cell generation. We investigated additional mechanisms by which IL-21/STAT3 signalling modulates human B-cell responses by studying patients with STAT3 mutations. IL-21 strongly induced CD25 (IL-2Ralpha) in normal, but not STAT3-deficient, CD40L-stimulated naive B cells. Chromatin immunoprecipitation confirmed IL2RA as a direct target of STAT3. IL-21-induced CD25 expression was also impaired on B cells from patients with IL2RG or IL21R mutations, confirming a requirement for intact IL-21R signalling in this process. IL-2 increased plasmablast generation and immunoglobulin secretion from normal, but not CD25-deficient, naive B cells stimulated with CD40L/IL-21. IL-2 and IL-21 were produced by T follicular helper cells, and neutralizing both cytokines abolished the B-cell helper capacity of these cells. Our results demonstrate that IL-21, via STAT3, sensitizes B cells to the stimulatory effects of IL-2. Thus, IL-2 may play an adjunctive role in IL-21-induced B-cell differentiation. Lack of this secondary effect of IL-21 may amplify the humoral immunodeficiency in patients with mutations in STAT3, IL2RG or IL21R due to impaired responsiveness to IL-21.
|Authors||Berglund, L. J.; Avery, D. T.; Ma, C. S.; Moens, L.; Deenick, E. K.; Bustamante, J.; Boisson-Dupuis, S.; Wong, M.; Adelstein, S.; Arkwright, P. D.; Bacchetta, R.; Bezrodnik, L.; Dadi, H.; Roifman, C.; Fulcher, D. A.; Ziegler, J. B.; Smart, J. M.; Kobayashi, M.; Picard, C.; Durandy, A.; Cook, M. C.; Casanova, J. L.; Uzel, G.; Tangye, S. G.;|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/24159173|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/11822|