title: PD-L2 modulates asthma severity by directly decreasing dendritic cell IL-12 production.
abstract: Studies examining the role of programmed death 1 (PD-1) ligand 2 (PD-L2)/PD-1 in asthma have yielded conflicting results. To clarify its role, we examined the PD-L2 expression in biopsies from human asthmatics and the lungs of aeroallergen-treated mice. PD-L2 expression in bronchial biopsies correlated with the severity of asthma. In mice, allergen exposure increased PD-L2 expression on pulmonary myeloid dendritic cells (DCs), and PD-L2 blockade diminished allergen-induced airway hyperresponsiveness (AHR). By contrast, PD-1 blockade had no impact, suggesting that PD-L2 promotes AHR in a PD-1-independent manner. Decreased AHR was associated with enhanced serum interleukin (IL)-12 p40, and in vitro stimulation of DCs with allergen and PD-L2-Fc reduced IL-12 p70 production, suggesting that PD-L2 inhibits allergen-driven IL-12 production. In our model, IL-12 did not diminish T helper type 2 responses but rather directly antagonized IL-13-inducible gene expression, highlighting a novel role for IL-12 in regulation of IL-13 signaling. Thus, allergen-driven enhancement of PD-L2 signaling through a PD-1-independent mechanism limits IL-12 secretion, exacerbating AHR.
authors.affiliation: Division of Cellular and Molecular Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. Ian.Lewkowich@cchmc.org
authors.forename: I P
authors.initials: IP
authors.lastname: Lewkowich
authors.forename: S
authors.initials: S
authors.lastname: Lajoie
authors.forename: S L
authors.initials: SL
authors.lastname: Stoffers
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.forename: P K
authors.initials: PK
authors.lastname: Richgels
authors.forename: K
authors.initials: K
authors.lastname: Dienger
authors.forename: A A
authors.initials: AA
authors.lastname: Sproles
authors.forename: H
authors.initials: H
authors.lastname: Yagita
authors.forename: Q
authors.initials: Q
authors.lastname: Hamid
authors.forename: M
authors.initials: M
authors.lastname: Wills-Karp
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D001249:Asthma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D007074:Immunoglobulin G / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis*; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D009093:Mucus / Q000378:metabolism; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000485:Allergens; D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D053762:Interleukin-12 Subunit p40; D018793:Interleukin-13; D061027:Programmed Cell Death 1 Ligand 2 Protein; D018664:Interleukin-12