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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1784-1793.
Prepublished online as a Blood First Edition Paper on June 25, 2008; DOI 10.1182/blood-2008-02-142745.
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Submitted February 28, 2008
Accepted June 4, 2008
STAT3 is required for IL-21-induced secretion of IgE from human naive B cells
Danielle T Avery, Cindy S Ma, Vanessa L Bryant, Brigitte Santner-Nanan, Ralph Nanan, Melanie Wong, David A Fulcher, Matthew C Cook, and Stuart G Tangye*
Immunology & Inflammation, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
Discipline of Paediatrics, Nepean Clinical School, University of Sydney, Penrith, NSW, Australia
Department of Immunology and Allergy, Children's Hospital, Westmead, Westmead, NSW, Australia
Immunology Unit, Institute of Clinical Pathology and Medical Research,, Westmead Hospital, Westmead, NSW, Australia
Department of Immunology, The Canberra Hospital, Woden, ACT, Australia
* Corresponding author; email: s.tangye{at}garvan.org.au.
The production of IgE is tightly regulated. This is evidenced by the fact that it comprises <0.0001% of serum Ig, and aberrant production causes atopic conditions including allergy, rhinitis and anaphylaxis. IL-4 is a well-characterised inducer of IgE by human and murine B cells, while IFN- can antagonise this effect. IL-21 has also been recognised for its ability to suppress IL-4-induced IgE production by murine B cells. Here, we identified IL-21 as an inducer of IgE production by CD40L-stimulated human naive B cells. Furthermore, there was a striking synergistic effect between IL-4 and IL-21 on inducing IgE secretion by all subsets of CD40L-stimulated human B cells, such that the levels detected under these conditions exceeded those induced by IL-4 or IL-21 alone by >10 fold. IL-21 induced activation of STAT3 and analysis of B cells from patients with loss-of-function STAT3 mutations revealed that the ability of IL-21 to induce IgE secretion, and augment that driven by IL-4, was STAT3-dependent. These findings highlight a fundamental difference between the regulation of IgE production by human and murine B cells and have implications for the dysregulated production of IgE in conditions characterised by extremely high levels of serum IgE.
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