title: Programmed Death Ligand 1 Promotes Early-Life Chlamydia Respiratory Infection-Induced Severe Allergic Airway Disease.
abstract: Chlamydia infections are frequent causes of respiratory illness, particularly pneumonia in infants, and are linked to permanent reductions in lung function and the induction of asthma. However, the immune responses that protect against early-life infection and the mechanisms that lead to chronic lung disease are incompletely understood. In the current study, we investigated the role of programmed death (PD)-1 and its ligands PD-L1 and PD-L2 in promoting early-life Chlamydia respiratory infection, and infection-induced airway hyperresponsiveness (AHR) and severe allergic airway disease in later life. Infection increased PD-1 and PD-L1, but not PD-L2, mRNA expression in the lung. Flow cytometric analysis of whole lung homogenates identified monocytes, dendritic cells, CD4(+), and CD8(+) T cells as major sources of PD-1 and PD-L1. Inhibition of PD-1 and PD-L1, but not PD-L2, during infection ablated infection-induced AHR in later life. Given that PD-L1 was the most highly up-regulated and its targeting prevented infection-induced AHR, subsequent analyses focused on this ligand. Inhibition of PD-L1 had no effect on Chlamydia load but suppressed infection-induced pulmonary inflammation. Infection decreased the levels of the IL-13 decoy receptor in the lung, which were restored to baseline levels by inhibition of PD-L1. Finally, inhibition of PD-L1 during infection prevented subsequent infection-induced severe allergic airways disease in later life by decreasing IL-13 levels, Gob-5 expression, mucus production, and AHR. Thus, early-life Chlamydia respiratory infection-induced PD-L1 promotes severe inflammation during infection, permanent reductions in lung function, and the development of more severe allergic airway disease in later life.
authors.affiliation: 1 Center for Asthma and Respiratory Disease and Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia; and.
authors.forename: Malcolm R
authors.initials: MR
authors.lastname: Starkey
authors.affiliation: 1 Center for Asthma and Respiratory Disease and Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia; and.
authors.forename: Duc H
authors.initials: DH
authors.lastname: Nguyen
authors.affiliation: 1 Center for Asthma and Respiratory Disease and Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia; and.
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Brown
authors.affiliation: 1 Center for Asthma and Respiratory Disease and Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia; and.
authors.forename: Ama-Tawiah
authors.initials: AT
authors.lastname: Essilfie
authors.affiliation: 1 Center for Asthma and Respiratory Disease and Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia; and.
authors.forename: Richard Y
authors.initials: RY
authors.lastname: Kim
authors.affiliation: 2 Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: 1 Center for Asthma and Respiratory Disease and Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia; and.
authors.forename: Jay C
authors.initials: JC
authors.lastname: Horvat
authors.affiliation: 1 Center for Asthma and Respiratory Disease and Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia; and.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Hansbro
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics / Q000502:physiology*; D002690:Chlamydia Infections / Q000150:complications*; D004198:Disease Susceptibility; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000209:etiology*; D012141:Respiratory Tract Infections / Q000150:complications*
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D053663:Interleukin-13 Receptor alpha2 Subunit; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger
keywords: Chlamydia respiratory infection; PD-L1; airway hyperresponsiveness; asthma; infant