Programmed death ligand 1 promotes early-life chlamydia respiratory infection-induced severe allergic airway disease

Malcolm R. Starkey, Duc H. Nguyen, Alexandra C. Brown, Ama Tawiah Essilfie, Richard Y. Kim, Hideo Yagita, Jay C. Horvat, Philip M. Hansbro

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16 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)493-503
Number of pages11
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume54
Issue number4
DOIs
Publication statusPublished - Apr 2016
Externally publishedYes

Keywords

  • Airway hyperresponsiveness
  • Asthma
  • Chlamydia respiratory infection
  • Infant
  • PD-L1

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