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IL-21 is the primary common gamma chain-binding cytokine required for human B-cell differentiation in vivo


Severe combined immunodeficiency (SCID) due to mutations in IL2RG or JAK3 is characterized by lack of T and NK cells; B cells are present in normal number but antibody responses are defective. Hematopoietic cell transplantation (HCT) is curative for SCID. However, B-cell dysfunction persists in a substantial proportion of patients. We hypothesized that impaired B-cell responses post-HCT in IL2RG/JAK3-deficiency results from poor donor B-cell engraftment and defective gammac-dependent cytokine signaling in host B cells. To test this, and to identify which gammac cytokine(s) are critical for humoral immunity, we studied 28 transplanted patients with IL2RG/JAK3-deficiency. Lack of donor B cell engraftment associated with persistent humoral dysfunction and significantly reduced memory B cells. B cell proliferation induced by CD40L alone or together with CpG, anti-Ig, IL-4, IL-10 or IL-13 was comparable in healthy controls and in post-HCT SCID patients, irrespective of their chimerism status. However, in vitro stimulation with CD40L/IL-21 induced B cell proliferation, plasmablast differentiation and antibody secretion in patients with donor B cells, but not those with autologous B cells. These data imply that IL-21-mediated signalling is critical for long-lived humoral immunity and to restore antibody responses in IL2RG/JAK3-deficient patients post-HCT. Furthermore, in vitro stimulation with CD40L/IL-21 can predict in vivo B cell immunity in IL2RG/JAK3 SCID post transplant.

Type Journal
Authors Recher, M.; Berglund, L. J.; Avery, D. T.; Cowan, M. J.; Gennery, A. R.; Smart, J.; Peake, J.; Wong, M.; Pai, S. Y.; Baxi, S.; Walter, J. E.; Palendira, U.; Tangye, G. A.; Rice, M.; Brothers, S.; Al-Herz, W.; Oettgen, H.; Eibel, H.; Puck, J. M.; Cattaneo, F.; Ziegler, J. B.; Giliani, S.; Tangye, S. G.; Notarangelo, L. D.:
Responsible Garvan Author Prof Stuart Tangye
Publisher Name Blood
Published Date 2011-12-31
Published Volume 118
Published Issue 26
Published Pages 6824-35
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version