Disruption of T helper 2-immune responses in Epstein-Barr virus-induced gene 3-deficient mice

Edward E.S. Nieuwenhuis, Markus F. Neurath, Nadia Corazza, Hideki Iijima, Joanne Trgovcich, Stefan Wirtz, Jonathan Glickman, Dan Bailey, Masaru Yoshida, Peter R. Galle, Mitchell Kronenberg, Mark Birkenbach, Richard S. Blumberg

Research output: Contribution to journalArticlepeer-review

147 Scopus citations

Abstract

Epstein-Barr virus-induced gene 3 (EBI3) is a widely expressed IL-12p40-related protein that associates as a heterodimer with either IL-12p35 or an IL-12p35 homologue, p28, to create a new cytokine (IL-27). To define the function of EBI3 in vivo, we generated knockout mice in which the ebi3 gene was targeted by homologous recombination. EBI3-/- mice exhibited normal numbers of both naive and mature CD4+ and CD8+ T cells and B cells, but markedly decreased numbers of invariant natural killer T cells (iNKT) as defined by staining with an α-galactosylceramide (αGalCer)-loaded CD1d-tetramer. iNKT cells from EBI3-/- mice exhibited decreased IL-4 and, to a lesser extent, IFN-γ production after αGalCer stimulation in vitro. A sustained decrease in IL-4 production was also observed in EBI3-/- mice after αGalCer stimulation in vivo in contrast to IFN-γ production, which was only transiently decreased under such stimulation. Notably, EBI3-/- mice were resistant to the induction of immunopathology associated with oxazolone-induced colitis, a colitis model mediated primarily by T helper (Th) 2-type cytokine production by iNKT cells. In contrast, trinitrobenzene sulfonic acid-induced colitis, a predominantly Th1-mediated colitis model, was unaffected. Thus, EBI3 plays a critical regulatory role in the induction of Th2-type immune responses and the development of Th2-mediated tissue inflammation in vivo, which may be mediated through the control of iNKT cell function.

Original languageEnglish (US)
Pages (from-to)16951-16956
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number26
DOIs
StatePublished - Dec 24 2002

Keywords

  • Colitis
  • Cytokines
  • Dendritic cells
  • Natural killer T cells
  • T helper cells

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