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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.

Original publication

DOI

10.1172/jci0215564

Type

Journal article

Journal

The Journal of clinical investigation

Publication Date

11/2002

Volume

110

Pages

1515 - 1523

Addresses

Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Department of Oncology and Pathology, Stockholm, Sweden.

Keywords

T-Lymphocytes, Cytotoxic, Tumor Cells, Cultured, Humans, Ovarian Neoplasms, Protein Sorting Signals, Lectins, C-Type, Receptors, Immunologic, Recombinant Proteins, Antigens, CD, Histocompatibility Antigens Class I, HLA-A Antigens, HLA-A2 Antigen, HLA Antigens, Signal Transduction, Cytotoxicity, Immunologic, Female, Interferon-gamma, NK Cell Lectin-Like Receptor Subfamily D, Receptors, Natural Killer Cell, NK Cell Lectin-Like Receptor Subfamily C, HLA-G Antigens, HLA-A11 Antigen