期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 99, 期 26, 页码 16951-16956出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.252648899
关键词
cytokines; colitis; T helper cells; dendritic cells; natural killer T cells
资金
- NCI NIH HHS [CA62375, T32 CA0954] Funding Source: Medline
- NIDDK NIH HHS [R01 DK044319, DK44319, R37 DK044319, DK53056, R01 DK053056, R01 DK051362, DK51362] Funding Source: Medline
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 a-galactosylceramide (alphaGalCer)-loaded CD1d-tetramer. iNKT cells from EBI3(-/-) mice exhibited decreased IL-4 and, to a lesser extent, IFN-gamma production after aGalCer stimulation in vitro. A sustained decrease in IL-4 production was also observed in EBI3(-/-) mice after aGalCer stimulation in vivo in contrast to IFN-y 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.
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