IL-21 signalling via STAT3 primes human naive B cells to respond to IL-2 to enhance their differentiation into plasmablasts.

Lucinda J. Berglund, Danielle T. Avery, Cindy S. Ma, Leen Moens, Elissa K. Deenick, Jacinta Bustamante, Stephanie Boisson-Dupuis, Melanie Wong, Stephen Adelstein, Peter D. Arkwright, Rosa Bacchetta, Liliana Bezrodnik, Harjit Dadi, Chaim M. Roifman, David A. Fulcher, John B. Ziegler, Joanne M. Smart, Masao Kobayashi, Capucine Picard, Anne DurandyMatthew C. Cook, Jean Laurent Casanova, Gulbu Uzel, Stuart G. Tangye

Research output: Contribution to journalArticlepeer-review

Abstract

B-cell responses are guided by the integration of signals through the B-cell receptor (BCR), CD40, and cytokine receptors. The common γ chain (γc)-binding cytokine interleukin (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 signaling modulates human B-cell responses by studying patients with STAT3 mutations. IL-21 strongly induced CD25 (IL-2Rα) in normal, but not STAT3-deficient, CD40L-stimulated naïve 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 signaling in this process. IL-2 increased plasmablast generation and immunoglobulin secretion from normal, but not CD25-deficient, naïve 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.

Original languageEnglish
Pages (from-to)3940-3950
Number of pages11
JournalBlood
Volume122
Issue number24
Publication statusPublished - Dec 5 2013

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology
  • Medicine(all)

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