Anti-Chlamydial Th17 Responses Are Controlled by the Inducible Costimulator Partially through Phosphoinositide 3-Kinase Signaling

We previously showed that mice deficient in the Inducible Costimulator ligand (ICOSL-KO) develop more severe disease and lung pathology with delayed bacterial clearance upon respiratory infection of Chlamydia muridarum. Importantly, the exacerbation of disease in ICOSL-KO mice was seen despite heigh...

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Vydáno v:	PloS one Ročník 7; číslo 12; s. e52657
Hlavní autoři:	Gao, Xiaoling, Gigoux, Mathieu, Yang, Jie, Leconte, Julien, Yang, Xi, Suh, Woong-Kyung
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 20.12.2012 Public Library of Science (PLoS)
Témata:	1-Phosphatidylinositol 3-kinase Analysis Animals Antibodies, Bacterial - immunology Antibody Formation - genetics Antibody Formation - immunology Apoptosis Bacteria Bacterial infections Bacterial Load Biology CD4 antigen Cell growth Chlamydia Chlamydia Infections - immunology Chlamydia Infections - metabolism Chlamydia Infections - microbiology Chlamydia muridarum - immunology Chlamydia trachomatis Cytokines Dendritic cells Development and progression Disease Models, Animal Female Health aspects Helper cells Immune clearance Immune response Immunology Inducible T-Cell Co-Stimulator Protein - genetics Inducible T-Cell Co-Stimulator Protein - metabolism Infection Infections Interferon Interferon-gamma - biosynthesis Interleukin 17 Laboratories Ligands Lung - immunology Lung - microbiology Lung - pathology Lung diseases Lymphocytes Lymphocytes T Medicine Mice Muridae Pathology Phosphatidylinositol 3-Kinases - metabolism Pneumonia Rodents Sexually transmitted diseases Signal Transduction Signaling Spleen - immunology Spleen - metabolism STD T cells Th17 Cells - immunology Th17 Cells - metabolism γ-Interferon Canada Manitoba Canada
ISSN:	1932-6203, 1932-6203
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Shrnutí:	We previously showed that mice deficient in the Inducible Costimulator ligand (ICOSL-KO) develop more severe disease and lung pathology with delayed bacterial clearance upon respiratory infection of Chlamydia muridarum. Importantly, the exacerbation of disease in ICOSL-KO mice was seen despite heightened IFN-γ/Th1 responses, the major defense mechanisms against Chlamydia. To gain insight into the mechanism of ICOS function in this model, we presently analyzed anti-Chlamydia immune responses in mice lacking the entire ICOS (ICOS-KO) versus knock-in mice expressing a mutant ICOS (ICOS-Y181F) that has selectively lost the ability to activate phosphoinositide 3-kinase (PI3K). Like ICOSL-KO mice, ICOS-KO mice showed worse disease with elevated IFN-γ/Th1 responses compared to wild-type (WT) mice. ICOS-Y181F mice developed much milder disease compared to ICOS-KO mice, yet they were still not fully protected to the WT level. This partial protection in ICOS-Y181F mice could not be explained by the magnitude of IFN-γ/Th1 responses since these mice developed a similar level of IFN-γ response compared to WT mice. It was rather IL-17/Th17 responses that reflected disease severity: IL-17/Th17 response was partially impaired in ICOS-Y181F mice compared to WT, but was substantially stronger than that of ICOS-KO mice. Consistently, we found that both polarization and expansion of Th17 cells were partially impaired in ICOS-Y181F CD4 T cells, and was further reduced in ICOS-KO CD4 T cells in vitro. Our results indicate that once the IFN-γ/Th1 response is above a threshold level, the IL-17/Th17 response becomes a limiting factor in controlling Chlamydia lung infection, and that ICOS plays an important role in promoting Th17 responses in part through the activation of PI3K.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Conceived and designed the experiments: W-KS XY. Performed the experiments: XG MG JY JL. Analyzed the data: XY W-KS. Wrote the paper: XG MG XY W-KS. Competing Interests: XY is a PLOS ONE Editorial Board member. The authors also confirm that this does not alter the authors adherence to all the PLOS ONE policies on sharing data and materials.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0052657