PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell-dependent airway hyperreactivity in opposing directions

O. Akbari, P. Stock, A. K. Singh, V. Lombardi, W. L. Lee, G. J. Freeman, A. H. Sharpe, D. T. Umetsu, R. H. DeKruyff

Research output: Contribution to journalArticlepeer-review

106 Scopus citations

Abstract

Interactions of the inhibitory receptor programmed death-1 (PD-1) with its ligands, programmed death ligand (PD-L)1 and PD-L2, regulate T-cell activation and tolerance. In this study, we investigated the role of PD-L1 and PD-L2 in regulating invariant natural killer T (iNKT)-cell-mediated airway hyperreactivity (AHR) in a murine model of asthma. We found that the severity of AHR and airway inflammation is significantly greater in PD-L2-/- mice compared with wild-type mice after either ovalbumin (OVA) sensitization and challenge or administration of α-galactosylceramide (α-GalCer). iNKT cells from PD-L2-/- mice produced significantly more interleukin (IL)-4 than iNKT cells from control mice. Moreover, blockade of PD-L2 interactions of wild-type iNKT cells in vitro with monoclonal antibodies (mAbs) resulted in significantly enhanced levels of IL-4 production. In contrast, PD-L1-/- mice showed significantly reduced AHR and enhanced production of interferon-γ (IFN-γ) by iNKT cells. iNKT-deficient Jα18-/- mice reconstituted with iNKT cells from PD-L2 -/- mice developed high levels of AHR, whereas mice reconstituted with iNKT cells from PD-L1-/- mice developed lower levels of AHR compared with control. As PD-L2 is not expressed on iNKT cells but rather is expressed on lung dendritic cells (DCs), in which its expression is upregulated by allergen challenge or IL-4, these findings suggest an important role of PD-L2 on lung DCs in modulating asthma pathogenesis. These studies also indicate that PD-L1 and PD-L2 have important but opposing roles in the regulation of AHR and iNKT-cell-mediated activation.

Original languageEnglish (US)
Pages (from-to)81-91
Number of pages11
JournalMucosal Immunology
Volume3
Issue number1
DOIs
StatePublished - Jan 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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