title: Oral-resident natural Th17 cells and γδ T cells control opportunistic Candida albicans infections.
abstract: Oropharyngeal candidiasis (OPC) is an opportunistic fungal infection caused by Candida albicans. OPC is frequent in HIV/AIDS, implicating adaptive immunity. Mice are naive to Candida, yet IL-17 is induced within 24 h of infection, and susceptibility is strongly dependent on IL-17R signaling. We sought to identify the source of IL-17 during the early innate response to candidiasis. We show that innate responses to Candida require an intact TCR, as SCID, IL-7Rα(-/-), and Rag1(-/-) mice were susceptible to OPC, and blockade of TCR signaling by cyclosporine induced susceptibility. Using fate-tracking IL-17 reporter mice, we found that IL-17 is produced within 1-2 d by tongue-resident populations of γδ T cells and CD3(+)CD4(+)CD44(hi)TCRβ(+)CCR6(+) natural Th17 (nTh17) cells, but not by TCR-deficient innate lymphoid cells (ILCs) or NK cells. These cells function redundantly, as TCR-β(-/-) and TCR-δ(-/-) mice were both resistant to OPC. Whereas γδ T cells were previously shown to produce IL-17 during dermal candidiasis and are known to mediate host defense at mucosal surfaces, nTh17 cells are poorly understood. The oral nTh17 population expanded rapidly after OPC, exhibited high TCR-β clonal diversity, and was absent in Rag1(-/-), IL-7Rα(-/-), and germ-free mice. These findings indicate that nTh17 and γδ T cells, but not ILCs, are key mucosal sentinels that control oral pathogens.
authors.affiliation: Division of Rheumatology and Clinical Immunology, and Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Department of Immunology, and Center for Biological Imaging, University of Pittsburgh, Pittsburgh, PA 15261.
authors.forename: Heather R
authors.initials: HR
authors.lastname: Conti
authors.affiliation: Division of Rheumatology and Clinical Immunology, and Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Department of Immunology, and Center for Biological Imaging, University of Pittsburgh, Pittsburgh, PA 15261.
authors.forename: Alanna C
authors.initials: AC
authors.lastname: Peterson
authors.affiliation: Division of Rheumatology and Clinical Immunology, and Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Department of Immunology, and Center for Biological Imaging, University of Pittsburgh, Pittsburgh, PA 15261.
authors.forename: Lucas
authors.initials: L
authors.lastname: Brane
authors.affiliation: Department of Infectious Diseases, Children's Hospital of Pittsburgh, Pittsburgh, PA 15224.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Huppler
authors.affiliation: Division of Rheumatology and Clinical Immunology, and Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Department of Immunology, and Center for Biological Imaging, University of Pittsburgh, Pittsburgh, PA 15261.
authors.forename: Nydiaris
authors.initials: N
authors.lastname: Hernández-Santos
authors.affiliation: Division of Rheumatology and Clinical Immunology, and Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Department of Immunology, and Center for Biological Imaging, University of Pittsburgh, Pittsburgh, PA 15261.
authors.forename: Natasha
authors.initials: N
authors.lastname: Whibley
authors.affiliation: Division of Rheumatology and Clinical Immunology, and Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Department of Immunology, and Center for Biological Imaging, University of Pittsburgh, Pittsburgh, PA 15261.
authors.forename: Abhishek V
authors.initials: AV
authors.lastname: Garg
authors.affiliation: Division of Rheumatology and Clinical Immunology, and Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Department of Immunology, and Center for Biological Imaging, University of Pittsburgh, Pittsburgh, PA 15261.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Simpson-Abelson
authors.affiliation: Division of Rheumatology and Clinical Immunology, and Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Department of Immunology, and Center for Biological Imaging, University of Pittsburgh, Pittsburgh, PA 15261.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Gibson
authors.affiliation: Division of Rheumatology and Clinical Immunology, and Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Department of Immunology, and Center for Biological Imaging, University of Pittsburgh, Pittsburgh, PA 15261.
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Mamo
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Osborne
authors.affiliation: Division of Rheumatology and Clinical Immunology, and Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Department of Immunology, and Center for Biological Imaging, University of Pittsburgh, Pittsburgh, PA 15261.
authors.forename: Shrinivas
authors.initials: S
authors.lastname: Bishu
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080.
authors.forename: Nico
authors.initials: N
authors.lastname: Ghilardi
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20852.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siebenlist
authors.affiliation: Division of Rheumatology and Clinical Immunology, and Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Department of Immunology, and Center for Biological Imaging, University of Pittsburgh, Pittsburgh, PA 15261.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: David
authors.initials: D
authors.lastname: Artis
authors.affiliation: Division of Rheumatology and Clinical Immunology, and Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Department of Immunology, and Center for Biological Imaging, University of Pittsburgh, Pittsburgh, PA 15261 Division of Rheumatology and Clinical Immunology, and Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Department of Immunology, and Center for Biological Imaging, University of Pittsburgh, Pittsburgh, PA 15261.
authors.forename: Mandy J
authors.initials: MJ
authors.lastname: McGeachy
authors.affiliation: Division of Rheumatology and Clinical Immunology, and Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Department of Immunology, and Center for Biological Imaging, University of Pittsburgh, Pittsburgh, PA 15261 Division of Rheumatology and Clinical Immunology, and Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Department of Immunology, and Center for Biological Imaging, University of Pittsburgh, Pittsburgh, PA 15261 sig65@pitt.edu.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gaffen
mesh_terms: D000818:Animals; D002176:Candida albicans / Q000276:immunology*; D002177:Candidiasis / Q000276:immunology / Q000517:prevention & control*; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000276:immunology*; D053759:Interleukin-23 / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009055:Mouth / Q000166:cytology / Q000276:immunology* / Q000382:microbiology; D060888:Real-Time Polymerase Chain Reaction; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000172:deficiency / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology*
chemical_list: C491673:Il17ra protein, mouse; D053759:Interleukin-23; D016692:Receptors, Antigen, T-Cell, gamma-delta; D053722:Receptors, Interleukin-17