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Serpin-6 Expression Protects Embryonic Stem Cells from Lysis by Antigen-Specific CTL¹

Zeinab Abdullah^2,*, Tomo Saric^2,, Hamid Kashkar^*, Nikola Baschuk^*, Benjamin Yazdanpanah^*, Bernd K. Fleischmann, Jürgen Hescheler, Martin Krönke^*, and Olaf Utermöhlen^3,*

^* Institute for Medical Microbiology, Immunology and Hygiene, Medical Center, University of Cologne, Cologne, Germany; Institute for Neurophysiology, Medical Center, University of Cologne, Cologne, Germany; Institute for Physiology I, Life and Brain Center, University of Bonn, Bonn, Germany; and Center for Molecular Medicine University of Cologne, Cologne, Germany

The immune response to embryonic stem (ES) cells is still poorly understood. In this study, we addressed the adaptive cellular immune response to undifferentiated and differentiated ES cells infected with lymphocytic choriomeningitis virus (LCMV), a vertically transmitted pathogen in mice and humans. In contrast to the prevailing view, we found that undifferentiated and differentiated murine ES cells express MHC class I molecules, although at low levels. When cocultured with LCMV-infected ES cells, syngeneic but not allogeneic LCMV-specific CTL secrete IFN-. Strikingly, LCMV-specific CTL do not efficiently kill LCMV-infected ES cells. ES cells showed high-level expression of the serine protease inhibitor 6, an endogenous inhibitor of the CTL-derived cytotoxic effector molecule granzyme B. Down-regulation of serpin-6 by RNA interference sensitized ES cells for CTL-induced cell death. The results of this study suggest that LCMV-infected murine ES cells present viral Ags and are recognized by LCMV-specific CTL in a MHC class I-restricted manner, yet resist CTL-mediated lysis through high-level expression of serine protease inhibitor 6.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Deutsche Forschungsgemeinschaft (to M.K. and T.S.), Imhoff Stiftung, Maria-Pesch Stiftung, and Köln Fortune Programm (to T.S. and O.U.).

² Z.A. and T.S. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Olaf Utermöhlen, Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Goldenfelsstrasse 19-21, 50935 Cologne, Germany. E-mail address: olaf.utermoehlen{at}uk-koeln.de

⁴ Abbreviations used in this paper: ES, embryonic stem; LIF, leukemia inhibiting factor; EB, embryoid body; LCMV, lymphocytic choriomeningitis virus; SPI-6, serine protease inhibitor 6; -Gal, -galactosidase; grz, granzyme; siRNA, small interfering RNA; shRNA, small hairpin RNA.

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