PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell-dependent airway hyperreactivity in opposing directions.
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.
Akbari
O
O
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. akbari@usc.edu
Stock
P
P
Singh
A K
AK
Lombardi
V
V
Lee
W-L
WL
Freeman
G J
GJ
Sharpe
A H
AH
Umetsu
D T
DT
Dekruyff
R H
RH
D000818:Animals; D019138:Antibodies, Blocking; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D060890:B7-H1 Antigen; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D005699:Galactosylceramides / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D008168:Lung / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010047:Ovalbumin / Q000276:immunology; D010455:Peptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D061027:Programmed Cell Death 1 Ligand 2 Protein
D019138:Antibodies, Blocking; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D005699:Galactosylceramides; D008562:Membrane Glycoproteins; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D015847:Interleukin-4; D007371:Interferon-gamma; D010047:Ovalbumin