title: Microbiota regulate the ability of lung dendritic cells to induce IgA class-switch recombination and generate protective gastrointestinal immune responses.
abstract: Protective immunoglobulin A (IgA) responses to oral antigens are usually orchestrated by gut dendritic cells (DCs). Here, we show that lung CD103(+) and CD24(+)CD11b(+) DCs induced IgA class-switch recombination (CSR) by activating B cells through T cell-dependent or -independent pathways. Compared with lung DCs (LDC), lung CD64(+) macrophages had decreased expression of B cell activation genes and induced significantly less IgA production. Microbial stimuli, acting through Toll-like receptors, induced transforming growth factor-β (TGF-β) production by LDCs and exerted a profound influence on LDC-mediated IgA CSR. After intranasal immunization with inactive cholera toxin (CT), LDCs stimulated retinoic acid-dependent up-regulation of α4β7 and CCR9 gut-homing receptors on local IgA-expressing B cells. Migration of these B cells to the gut resulted in IgA-mediated protection against an oral challenge with active CT. However, in germ-free mice, the levels of LDC-induced, CT-specific IgA in the gut are significantly reduced. Herein, we demonstrate an unexpected role of the microbiota in modulating the protective efficacy of intranasal vaccination through their effect on the IgA class-switching function of LDCs.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029 The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Darren
authors.initials: D
authors.lastname: Ruane
authors.affiliation: The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Alejo
authors.initials: A
authors.lastname: Chorny
authors.affiliation: Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029 The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Haekyung
authors.initials: H
authors.lastname: Lee
authors.affiliation: The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Jeremiah
authors.initials: J
authors.lastname: Faith
authors.affiliation: Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Pandey
authors.affiliation: The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Meimei
authors.initials: M
authors.lastname: Shan
authors.affiliation: The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Noa
authors.initials: N
authors.lastname: Simchoni
authors.affiliation: The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Adeeb
authors.initials: A
authors.lastname: Rahman
authors.affiliation: Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Aakash
authors.initials: A
authors.lastname: Garg
authors.affiliation: The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Erica G
authors.initials: EG
authors.lastname: Weinstein
authors.affiliation: The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Michael
authors.initials: M
authors.lastname: Oropallo
authors.affiliation: Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029 The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Michelle
authors.initials: M
authors.lastname: Gaylord
authors.affiliation: Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Ryan
authors.initials: R
authors.lastname: Ungaro
authors.affiliation: The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Cunningham-Rundles
authors.affiliation: The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Alexandropoulos
authors.affiliation: Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mucida
authors.affiliation: The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Miriam
authors.initials: M
authors.lastname: Merad
authors.affiliation: The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cerutti
authors.affiliation: Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029 The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Mehandru
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D053264:B-Cell Activating Factor / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051927:CD24 Antigen / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D015870:Gene Expression; D007070:Immunoglobulin A / Q000235:genetics* / Q000276:immunology*; D017578:Immunoglobulin Class Switching / Q000187:drug effects / Q000235:genetics*; D039001:Integrin alpha Chains / Q000378:metabolism; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D051379:Mice; D064307:Microbiota; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D054388:Receptors, CCR / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D015703:Antigens, CD; D053264:B-Cell Activating Factor; D051927:CD24 Antigen; D007070:Immunoglobulin A; D039001:Integrin alpha Chains; D016023:Integrins; D053594:Myeloid Differentiation Factor 88; D054388:Receptors, CCR; D016212:Transforming Growth Factor beta; D014212:Tretinoin; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; C119309:CC chemokine receptor 9; C476286:Ticam1 protein, mouse; C091367:alpha E integrins; C071777:integrin alpha4beta7