DNAX accessory molecule-1 (CD226) promotes human hepatocellular carcinoma cell lysis by Vgamma9Vdelta2 T cells.
Human Vgamma9Vdelta2 T lymphocytes can be activated by nonpeptidic antigens such as the mevalonate pathway-derived isopentenyl pyrophosphate or synthetic phosphoantigen such as bromohydrin pyrophosphate. They display a strong cytotoxic activity against several tumor types, including hepatocellular carcinoma (HCC). Little is known about the mechanisms underlying Vgamma9Vdelta2 T-cell recognition of tumor cells, but there is strong evidence that activating NK receptors play a role in gammadelta T-cell cytotoxicity. In this study, we showed that the two NK receptors DNAX accessory molecule-1 (DNAM-1) and CD96 were expressed by Vgamma9Vdelta2 T cells. The ligands Nectin-like-5 specific of both DNAM-1 and CD96, and also Nectin-2, an additional ligand of DNAM-1, were present on all HCC cell lines analyzed. Furthermore, we demonstrated by mAb-mediated masking experiments that cytotoxicity against HCC cells as well as IFN-gamma production in gammadelta T cells were dependent on DNAM-1. Our experiments indicated that Nectin-like-5 but not Nectin-2 was involved in DNAM-1-dependent gammadelta T-cell functions. We did not reveal a role for CD96 in the killing of HCC cells. Finally, we showed by combined mAb-mediated blockade that DNAM-1 and NKG2D could cooperate in the cell lysis of HCC.
Toutirais
Olivier
O
EE 341 Biothérapies Innovantes, Faculté de Médecine, Université de Rennes 1, Rennes, France.
Cabillic
Florian
F
Le Friec
Gaëlle
G
Salot
Samuel
S
Loyer
Pascal
P
Le Gallo
Matthieu
M
Desille
Mireille
M
de La Pintière
Cécile Thomas
CT
Daniel
Pascale
P
Bouet
Françoise
F
Catros
Véronique
V
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000276:immunology*; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000628:therapy; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007167:Immunotherapy / Q000379:methods; D008113:Liver Neoplasms / Q000276:immunology* / Q000628:therapy; D008213:Lymphocyte Activation; D000075983:Nectins; D034741:RNA, Small Interfering / Q000235:genetics; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection; D000098862:T Lineage-Specific Activation Antigen 1
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; C116131:CD96 antigen; D015815:Cell Adhesion Molecules; D000075983:Nectins; D034741:RNA, Small Interfering; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011991:Receptors, Virus; C066100:poliovirus receptor