title: IFN-gamma protects short-term ovarian carcinoma cell lines from CTL lysis via a CD94/NKG2A-dependent mechanism.
abstract: IFN-gamma regulates the immunogenicity of target cells by increasing their expression of HLA class I molecules. This facilitates the T cell receptor-mediated recognition by CD8(+) T cells but decreases target cell sensitivity to lysis by NK cells due to engagement of inhibitory NK receptors. In this study, short-term tumor cell lines from patients with advanced ovarian carcinomas were established. We demonstrate the paradoxical finding that IFN-gamma treatment of these short-term ovarian carcinoma cell lines (OVACs) resulted in resistance of tumor cells to lysis by peptide- and allospecific CD8(+) T cells. Blocking experiments revealed that this phenomenon was dependent on enhanced inhibitory signalling via CD94/NKG2A receptors expressed on the effector cells. This was associated with increased expression of HLA-E mRNA and HLA-G at the protein level in IFN-gamma-treated OVACs. Furthermore, pulsing of untreated OVACs with the leader sequence peptide of HLA-G protected these cells from lysis by CTLs, thus mimicking the inhibitory effect of IFN-gamma. This study provides evidence that CD94/NKG2A receptors play an important role in regulating T cell activity against tumors and shows that IFN-gamma modulation of target cells may shift the balance of triggering and inhibitory signals to T cells, turning off their cytolytic activity.
authors.affiliation: Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Department of Oncology and Pathology, Stockholm, Sweden.
authors.forename: Karl-Johan
authors.initials: KJ
authors.lastname: Malmberg
authors.forename: Victor
authors.initials: V
authors.lastname: Levitsky
authors.forename: Håkan
authors.initials: H
authors.lastname: Norell
authors.forename: Cristina Teixeira
authors.initials: CT
authors.lastname: de Matos
authors.forename: Mattias
authors.initials: M
authors.lastname: Carlsten
authors.forename: Kjell
authors.initials: K
authors.lastname: Schedvins
authors.forename: Hodjattallah
authors.initials: H
authors.lastname: Rabbani
authors.forename: Alessandro
authors.initials: A
authors.lastname: Moretta
authors.forename: Kalle
authors.initials: K
authors.lastname: Söderström
authors.forename: Jelena
authors.initials: J
authors.lastname: Levitskaya
authors.forename: Rolf
authors.initials: R
authors.lastname: Kiessling
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D006680:HLA Antigens / Q000378:metabolism; D015234:HLA-A Antigens / Q000378:metabolism; D059870:HLA-A11 Antigen; D015789:HLA-A2 Antigen / Q000378:metabolism; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D037181:Lectins, C-Type / Q000378:metabolism*; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D010051:Ovarian Neoplasms / Q000276:immunology*; D021382:Protein Sorting Signals; D011971:Receptors, Immunologic / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D011994:Recombinant Proteins; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; D006680:HLA Antigens; D015234:HLA-A Antigens; D059870:HLA-A11 Antigen; D015789:HLA-A2 Antigen; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; C527054:KLRC1 protein, human; C497869:KLRD1 protein, human; D037181:Lectins, C-Type; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D021382:Protein Sorting Signals; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D011994:Recombinant Proteins; D007371:Interferon-gamma