IFN-γ protects short-term ovarian carcinoma cell lines from CTL lysis via a CD94/NKG2A-dependent mechanism

• Published in: The Journal of clinical investigation 2002-11, Vol.110 (10), p.1515-1523
• Main Authors: Malmberg, Karl-Johan, Levitsky, Victor, Norell, Håkan, Matos, Cristina Teixeira de, Carlsten, Mattias, Schedvins, Kjell, Rabbani, Hodjattallah, Moretta, Alessandro, Söderström, Kalle, Levitskaya, Jelena, Kiessling, Rolf
• Format: Article
• Language: English
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI15564

IFN-γ 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-γ 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-γ–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-γ. This study provides evidence that CD94/NKG2A receptors play an important role in regulating T cell activity against tumors and shows that IFN-γ modulation of target cells may shift the balance of triggering and inhibitory signals to T cells, turning off their cytolytic activity.