Abstract
Epstein-Barr virus-induced gene 3 (EBI3) associates with p28 to form IL-27 and with IL-12p35 to form IL-35. IL-27Ralpha(-/-) mice studies indicate that IL-27 negatively regulates Th17 cell differentiation. However, no EBI3, p28 or p35-deficiency studies that directly address the role of EBI3, p28 or p35 on Th17 cells have been done. Here, we demonstrate that spleen cells derived from EBI3(-/-) mice produce significantly higher levels of IL-17 as well as IL-22 upon stimulation with OVA. In vitro derived EBI3(-/-) Th17 cells also produced significantly higher levels of IL-17 and IL-22 than WT cells. The frequency of IL-17-producing cells was also elevated when EBI3(-/-) cells were cultured under Th17 conditions. In addition, spleen cells from EBI3(-/-) mice immunized with Listeria monocytogenes produced significantly elevated levels of IL-17 and IL-22. Furthermore, the Th17 transcription factor RORgamma t was significantly enhanced in EBI3(-/-) cells. Finally, EBI3(-/-) mice exhibited a reduced bacterial load following an acute challenge with L. monocytogenes or a re-challenge of previously immunized mice, suggesting that EBI3 negatively regulates both innate and adaptive immunity. Taken together, these data provide direct evidence that EBI3 negatively regulates the expression of IL-17, IL-22 and RORgamma t as well as protective immunity against L. monocytogenes.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CD4-Positive T-Lymphocytes / metabolism
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Cell Differentiation / immunology
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism
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Gene Expression / genetics
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Gene Expression Regulation*
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Interferon-gamma / blood
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Interferon-gamma / genetics
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Interferon-gamma / metabolism
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Interleukin-17 / blood
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Interleukin-17 / genetics
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Interleukin-17 / metabolism*
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Interleukin-22
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Interleukins / genetics*
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Interleukins / metabolism*
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Listeria monocytogenes / immunology
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Listeriosis / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Minor Histocompatibility Antigens
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Nuclear Receptor Subfamily 1, Group F, Member 3
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Ovalbumin / immunology
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / immunology
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Receptors, Retinoic Acid / genetics*
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Receptors, Thyroid Hormone / genetics*
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Spleen / cytology
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Spleen / microbiology
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism*
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
Substances
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EBI3 protein, human
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Interleukin-17
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Interleukins
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Minor Histocompatibility Antigens
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Nuclear Receptor Subfamily 1, Group F, Member 3
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RORC protein, human
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Receptors, Antigen, T-Cell
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Receptors, Retinoic Acid
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Receptors, Thyroid Hormone
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Rorc protein, mouse
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Tumor Necrosis Factor-alpha
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Interferon-gamma
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Ovalbumin