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

Karl Johan Malmberg, Victor Levitsky, Håkan Norell, Cristina Teixeira De Matos, Mattias Carlsten, Kjell Schedvins, Hodjattallah Rabbani, Alessandro Moretta, Kalle Söderström, Jelena Levitskaya, Rolf Kiessling

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1515-1523
Number of pages9
JournalJournal of Clinical Investigation
Volume110
Issue number10
DOIs
StatePublished - Nov 2002
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Malmberg, K. J., Levitsky, V., Norell, H., De Matos, C. T., Carlsten, M., Schedvins, K., Rabbani, H., Moretta, A., Söderström, K., Levitskaya, J., & Kiessling, R. (2002). IFN-γ protects short-term ovarian carcinoma cell lines from CTL lysis via a CD94/NKG2A-dependent mechanism. Journal of Clinical Investigation, 110(10), 1515-1523. https://doi.org/10.1172/JCI200215564