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

EES 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 journalArticleAcademicpeer-review

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 alpha-galactosylceramide (alphaGalCer)-loaded CD1d-tetramer. iNKT cells from EBI3-/- mice exhibited decreased IL-4 and, to a lesser extent, IFN-gamma production after alphaGalCer stimulation in vitro. A sustained decrease in IL-4 production was also observed in EBI3-/- mice after alphaGalCer stimulation in vivo in contrast to IFN-gamma 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
Pages (from-to)16951-6
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number26
DOIs
Publication statusPublished - 24 Dec 2002

Keywords

  • Animals
  • Glycoproteins
  • Interferon-gamma
  • Interleukin-4
  • Interleukins
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Cytokine
  • T-Lymphocytes
  • Th2 Cells

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