title: Pulmonary Th17 Antifungal Immunity Is Regulated by the Gut Microbiome.
abstract: Commensal microbiota are critical for the development of local immune responses. In this article, we show that gut microbiota can regulate CD4 T cell polarization during pulmonary fungal infections. Vancomycin drinking water significantly decreased lung Th17 cell numbers during acute infection, demonstrating that Gram-positive commensals contribute to systemic inflammation. We next tested a role for RegIIIγ, an IL-22-inducible antimicrobial protein with specificity for Gram-positive bacteria. Following infection, increased accumulation of Th17 cells in the lungs of RegIIIγ(-/-) and Il22(-/-) mice was associated with intestinal segmented filamentous bacteria (SFB) colonization. Although gastrointestinal delivery of rRegIIIγ decreased lung inflammatory gene expression and protected Il22(-/-) mice from weight loss during infection, it had no direct effect on SFB colonization, fungal clearance, or lung Th17 immunity. We further show that vancomycin only decreased lung IL-17 production in mice colonized with SFB. To determine the link between gut microbiota and lung immunity, serum-transfer experiments revealed that IL-1R ligands increase the accumulation of lung Th17 cells. These data suggest that intestinal microbiota, including SFB, can regulate pulmonary adaptive immune responses.
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA 15224;
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: McAleer
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA 15224; Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112;
authors.forename: Nikki L H
authors.initials: NL
authors.lastname: Nguyen
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA 15224;
authors.forename: Kong
authors.initials: K
authors.lastname: Chen
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA 15224;
authors.forename: Pawan
authors.identifier: 0000-0003-1522-4122
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA 15224; Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112;
authors.forename: David M
authors.identifier: 0000-0002-6266-7105
authors.initials: DM
authors.lastname: Ricks
authors.affiliation: Division of Respirology, Department of Medicine, University of Toronto, Ontario M5B 1W8, Canada;
authors.forename: Matthew
authors.identifier: 0000-0001-8665-1389
authors.initials: M
authors.lastname: Binnie
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA 15224;
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Armentrout
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA 15224;
authors.forename: Derek A
authors.identifier: 0000-0002-1256-6410
authors.initials: DA
authors.lastname: Pociask
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA 15224;
authors.forename: Aaron
authors.identifier: 0000-0002-8867-6122
authors.initials: A
authors.lastname: Hein
authors.affiliation: Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112;
authors.forename: Amy
authors.identifier: 0000-0002-1144-3371
authors.initials: A
authors.lastname: Yu
authors.affiliation: Department of Civil and Environmental Engineering, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: Amit
authors.initials: A
authors.lastname: Vikram
authors.affiliation: Department of Civil and Environmental Engineering, University of Pittsburgh, Pittsburgh, PA 15261; Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260;
authors.forename: Kyle
authors.identifier: 0000-0003-3142-6090
authors.initials: K
authors.lastname: Bibby
authors.affiliation: Yakult Central Institute for Microbiological Research, Kunitachi-shi, Tokyo 186-8650, Japan;
authors.forename: Yoshinori
authors.identifier: 0000-0003-2422-9187
authors.initials: Y
authors.lastname: Umesaki
authors.affiliation: Department of Pediatrics, Center for Immunity and Inflammation, New Jersey Medical School, Newark, NJ 07101;
authors.forename: Amariliz
authors.initials: A
authors.lastname: Rivera
authors.affiliation: Lung Biology Center, University of California, San Francisco, San Francisco, CA 94143;
authors.forename: Dean
authors.identifier: 0000-0002-6277-2036
authors.initials: D
authors.lastname: Sheppard
authors.affiliation: Department of Immunology, Genentech, South San Francisco, CA 94080; and.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ouyang
authors.affiliation: Department of Immunology, Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Lora V
authors.initials: LV
authors.lastname: Hooper
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA 15224; jay.kolls@chp.edu.
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001228:Aspergillosis / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000276:immunology*; D002478:Cells, Cultured; D000069196:Gastrointestinal Microbiome / Q000276:immunology*; D006094:Gram-Positive Bacteria / Q000276:immunology*; D007109:Immunity / Q000187:drug effects; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology*; D014640:Vancomycin / Q000627:therapeutic use; D000097043:Interleukin-22
chemical_list: D000900:Anti-Bacterial Agents; D007378:Interleukins; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; D014640:Vancomycin; D000097043:Interleukin-22; C490255:Reg3g protein, mouse