@article {542321,
	title = {PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell-dependent airway hyperreactivity in opposing directions.},
	journal = {Mucosal Immunol},
	volume = {3},
	number = {1},
	year = {2010},
	month = {2010 Jan},
	pages = {81-91},
	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 alpha-galactosylceramide (alpha-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-gamma (IFN-gamma) by iNKT cells. iNKT-deficient Jalpha18(-/-) 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.},
	keywords = {Animals, Antibodies, Blocking, Antigens, CD274, Antigens, CD80, Asthma, Cells, Cultured, Dendritic Cells, Female, Galactosylceramides, Interferon-gamma, Interleukin-4, Lung, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Knockout, Natural Killer T-Cells, Ovalbumin, Peptides, Programmed Cell Death 1 Ligand 2 Protein},
	issn = {1935-3456},
	doi = {10.1038/mi.2009.112},
	author = {Akbari, O and Stock, P and Singh, A K and Lombardi, V and Lee, W-L and Freeman, G. J. and Sharpe, A. H. and Umetsu, D T and Dekruyff, R H}
}
