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

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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
Externally publishedYes

Fingerprint

Natural Killer T-Cells
Inflammation
Interleukin-4
Programmed Cell Death 1 Ligand 2 Protein
Dendritic Cells
Asthma
Galactosylceramides
Direction compound
Lung
Death Domain Receptors
Ovalbumin
Allergens
Interferons
Monoclonal Antibodies
Ligands
T-Lymphocytes

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Akbari, O., Stock, P., Singh, A. K., Lombardi, V., Lee, W. L., Freeman, G. J., ... DeKruyff, R. H. (2010). PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell-dependent airway hyperreactivity in opposing directions. Mucosal Immunology, 3(1), 81-91. https://doi.org/10.1038/mi.2009.112

PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell-dependent airway hyperreactivity in opposing directions. / Akbari, O.; Stock, P.; Singh, A. K.; Lombardi, V.; Lee, W. L.; Freeman, G. J.; Sharpe, A. H.; Umetsu, D. T.; DeKruyff, R. H.

In: Mucosal Immunology, Vol. 3, No. 1, 01.2010, p. 81-91.

Research output: Contribution to journalArticle

Akbari, O, Stock, P, Singh, AK, Lombardi, V, Lee, WL, Freeman, GJ, Sharpe, AH, Umetsu, DT & DeKruyff, RH 2010, 'PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell-dependent airway hyperreactivity in opposing directions', Mucosal Immunology, vol. 3, no. 1, pp. 81-91. https://doi.org/10.1038/mi.2009.112
Akbari, O. ; Stock, P. ; Singh, A. K. ; Lombardi, V. ; Lee, W. L. ; Freeman, G. J. ; Sharpe, A. H. ; Umetsu, D. T. ; DeKruyff, R. H. / PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell-dependent airway hyperreactivity in opposing directions. In: Mucosal Immunology. 2010 ; Vol. 3, No. 1. pp. 81-91.
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