title: HLA-G inhibition of NK-cell cytolytic function is uncoupled from tumor cell lipid raft reorganization.
abstract: HLA-G is a non-classical HLA class I molecule with tolerogenic properties and restricted tissue distribution. The expression of HLA-G can be induced by tumors thus providing an efficient way to escape the anti-tumoral immune response. Although lipid rafts regulate diverse immunological mechanisms their relationship with HLA-G remains controversial. Our results show that HLA-G-mediated inhibition of both the interaction between NK and tumor cells, and of intracellular calcium flux in NK cells conjugated to their target cells were independent of lipid raft integrity. In addition, cytotoxicity assays indicated that HLA-G continued to efficiently inhibit NK-cell cytolytic function in several different tumor cells independently of lipid raft integrity. Confocal microscopy with 3D reconstruction combined with biochemical analysis showed that HLA-G was mainly localized outside the lipid rafts of tumor cells after cross-linking with specific antibody and remained excluded from lipid rafts during interaction with the ILT2 inhibitory receptor of NK cells. This study indicates that the inhibitory function of HLA-G is uncoupled from lipid raft organization, further distinguishing HLA-G from classical HLA molecules and providing novel information in the understanding of tumor immune escape mechanism mediated through HLA-G.
authors.affiliation: CEA, I²BM, Service de Recherches en Hemato-Immunologie, F-75475, Paris, France.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Baudhuin
authors.forename: Emilie
authors.initials: E
authors.lastname: Lesport
authors.forename: Sylvie
authors.initials: S
authors.lastname: Sousa
authors.forename: Julie
authors.initials: J
authors.lastname: Migraine
authors.forename: James
authors.initials: J
authors.lastname: Vigneron
authors.forename: Joel
authors.initials: J
authors.lastname: Lemaoult
authors.forename: Edgardo D
authors.initials: ED
authors.lastname: Carosella
authors.forename: Nuala
authors.initials: N
authors.lastname: Mooney
authors.forename: Benoit
authors.initials: B
authors.lastname: Favier
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005434:Flow Cytometry; D059951:HLA-G Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000648:ultrastructure; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008545:Melanoma / Q000276:immunology*; D021962:Membrane Microdomains / Q000276:immunology* / Q000648:ultrastructure; D018613:Microscopy, Confocal; D011971:Receptors, Immunologic / Q000276:immunology; D019139:Tumor Escape / Q000276:immunology; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D059951:HLA-G Antigens; C105299:LILRB1 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D011971:Receptors, Immunologic; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin