IFN-gamma-mediated inhibition of human IgE synthesis by IL-21 is associated with a polymorphism in the IL-21R gene

J Immunol. 2006 Oct 15;177(8):5006-13. doi: 10.4049/jimmunol.177.8.5006.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology
  • Cell Proliferation
  • Cells, Cultured
  • Heterozygote
  • Humans
  • Immunoglobulin E / biosynthesis*
  • Immunologic Memory
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / physiology*
  • Interleukin-4 / pharmacology
  • Interleukins / physiology*
  • Leukocytes / cytology
  • Lymphocyte Activation / immunology
  • Polymorphism, Genetic*
  • Receptors, Interleukin-21 / genetics*
  • Spleen / cytology

Substances

  • Interleukins
  • Receptors, Interleukin-21
  • Interleukin-4
  • Immunoglobulin E
  • Interferon-gamma
  • interleukin-21