IFN-gamma-mediated inhibition of human IgE synthesis by IL-21 is associated with a polymorphism in the IL-21R gene.
IL-21 is a cytokine produced by CD4+ T cells that has been reported to regulate human, as well as, mouse T and NK cell function and to inhibit Ag-induced IgE production by mouse B cells. In the present study, we show that human rIL-21 strongly enhances IgE production by both CD19+ CD27- naive, and CD19+ CD27+ memory B cells, stimulated with anti-CD40 mAb and rIL-4 and that it promotes the proliferative responses of these cells. However, rIL-21 does not significantly affect anti-CD40 mAb and rIL-4-induced Cepsilon promoter activation in a gene reporter assay, nor germline Cepsilon mRNA expression in purified human spleen or peripheral blood B cells. In contrast, rIL-21 inhibits rIL-4-induced IgE production in cultures of PBMC or total splenocytes by an IFN-gamma-dependent mechanism. The presence of a polymorphism (T-83C), in donors heterozygous for this mutation was found to be associated not only with lower rIL-21-induced IFN-gamma production levels, but also with a lower sensitivity to the inhibitory effects of IL-21 on the production of IgE, compared with those in donors expressing the wild-type IL-21R. Taken together, these results show that IL-21 differentially regulates IL-4-induced human IgE production, via its growth- and differentiation-promoting capacities on isotype-, including IgE-, committed B cells, as well as via its ability to induce IFN-gamma production, most likely by T and NK cells, whereas the outcome of these IL-21-mediated effects is dependent on the presence of a polymorphism in the IL-21R.
Pène
Jérôme
J
Institut National de la Santé et de la Recherche Médicale, Unité 454, Centre Hospitalier Universitaire St. Eloi, Montpellier, France.
Guglielmi
Laurence
L
Gauchat
Jean-François
JF
Harrer
Nathalie
N
Woisetschläger
Maximilian
M
Boulay
Vera
V
Fabre
Jean-Michel
JM
Demoly
Pascal
P
Yssel
Hans
H
D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D006579:Heterozygote; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis*; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology*; D015847:Interleukin-4 / Q000494:pharmacology; D007378:Interleukins / Q000502:physiology*; D007962:Leukocytes / Q000166:cytology; D008213:Lymphocyte Activation / Q000276:immunology; D011110:Polymorphism, Genetic; D053655:Receptors, Interleukin-21 / Q000235:genetics*; D013154:Spleen / Q000166:cytology; D000098546:Interleukin-21
D007378:Interleukins; D053655:Receptors, Interleukin-21; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma; D000098546:Interleukin-21