title: PD-1/PD-L blockade prevents anergy induction and enhances the anti-tumor activities of glycolipid-activated invariant NKT cells.
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.
authors.affiliation: Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Vrajesh V
authors.initials: VV
authors.lastname: Parekh
authors.forename: Saif
authors.initials: S
authors.lastname: Lalani
authors.forename: Sungjune
authors.initials: S
authors.lastname: Kim
authors.forename: Ramesh
authors.initials: R
authors.lastname: Halder
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Vipin
authors.initials: V
authors.lastname: Kumar
authors.forename: Lan
authors.initials: L
authors.lastname: Wu
authors.forename: Luc Van
authors.initials: LV
authors.lastname: Kaer
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology; D060890:B7-H1 Antigen; D017635:Clonal Anergy / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D005260:Female; D005699:Galactosylceramides / Q000502:physiology* / Q000627:therapeutic use; D014644:Genetic Variation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology*; D010455:Peptides / Q000037:antagonists & inhibitors* / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D005699:Galactosylceramides; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; C493154:alpha-galactosylceramide