• O Akbari, P Stock, A K Singh, V Lombardi, W-L Lee, G J Freeman, A H Sharpe, D T Umetsu, and R H Dekruyff.
• Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. akbari@usc.edu
• Mucosal Immunol. 2010 Jan 1; 3 (1): 81-91.

AbstractInteractions 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.

49 keywords...

hide…