title: Anti-chlamydial Th17 responses are controlled by the inducible costimulator partially through phosphoinositide 3-kinase signaling.
abstract: 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.
authors.affiliation: Laboratory of Infection and Immunity, Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Gao
authors.forename: Mathieu
authors.initials: M
authors.lastname: Gigoux
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Julien
authors.initials: J
authors.lastname: Leconte
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.forename: Woong-Kyung
authors.initials: WK
authors.lastname: Suh
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D000917:Antibody Formation / Q000235:genetics / Q000276:immunology; D058491:Bacterial Load; D002690:Chlamydia Infections / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D023502:Chlamydia muridarum / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000907:Antibodies, Bacterial; D060889:Inducible T-Cell Co-Stimulator Protein; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases