RRC ID 37679
Author Parekh VV, Lalani S, Kim S, Halder R, Azuma M, Yagita H, Kumar V, Wu L, Kaer LV.
Title PD-1/PD-L blockade prevents anergy induction and enhances the anti-tumor activities of glycolipid-activated invariant NKT cells.
Journal J. Immunol.
Abstract Invariant NKT (iNKT) cells recognize glycolipid Ags, such as the marine sponge-derived glycosphingolipid alpha-galactosylceramide (alphaGalCer) presented by the CD1d protein. In vivo activation of iNKT cells with alphaGalCer results in robust cytokine production, followed by the acquisition of an anergic phenotype. Here we have investigated mechanisms responsible for the establishment of alphaGalCer-induced iNKT cell anergy. We found that alphaGalCer-activated iNKT cells rapidly up-regulated expression of the inhibitory costimulatory receptor programmed death (PD)-1 at their cell surface, and this increased expression was retained for at least one month. Blockade of the interaction between PD-1 and its ligands, PD-L1 and PD-L2, at the time of alphaGalCer treatment prevented the induction iNKT cell anergy, but was unable to reverse established iNKT cell anergy. Consistently, injection of alphaGalCer into PD-1-deficient mice failed to induce iNKT cell anergy. However, blockade of the PD-1/PD-L pathway failed to prevent bacterial- or sulfatide-induced iNKT cell anergy, suggesting additional mechanisms of iNKT cell tolerance. Finally, we showed that blockade of PD-1/PD-L interactions enhanced the antimetastatic activities of alphaGalCer. Collectively, our findings reveal a critical role for the PD-1/PD-L costimulatory pathway in the alphaGalCer-mediated induction of iNKT cell anergy that can be targeted for the development of immunotherapies.
Volume 182(5)
Pages 2816-26
Published 2009-3-1
DOI 10.4049/jimmunol.0803648
PII 182/5/2816
PMID 19234176
PMC PMC2709814
MeSH Animals Antigens, Surface / immunology Apoptosis Regulatory Proteins / antagonists & inhibitors* Apoptosis Regulatory Proteins / deficiency Apoptosis Regulatory Proteins / immunology B7-1 Antigen / immunology B7-H1 Antigen Clonal Anergy / immunology* Cytotoxicity, Immunologic* Female Galactosylceramides / physiology* Galactosylceramides / therapeutic use Genetic Variation / immunology* Lymphocyte Activation / immunology Melanoma, Experimental / immunology* Melanoma, Experimental / pathology Melanoma, Experimental / therapy Membrane Glycoproteins / antagonists & inhibitors* Membrane Glycoproteins / immunology Mice Mice, Inbred C57BL Mice, Knockout Natural Killer T-Cells / cytology Natural Killer T-Cells / immunology* Peptides / antagonists & inhibitors* Peptides / immunology Programmed Cell Death 1 Receptor Signal Transduction / immunology
IF 4.539
Times Cited 90
Human and Animal Cells