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Dendritic Cells Treated with Lipopolysaccharide Up-Regulate Serine Protease Inhibitor 6 and Remain Sensitive to Killing by Cytotoxic T Lymphocytes In Vivo¹

Malaghan Institute of Medical Research, Wellington, New Zealand

Ag presentation by dendritic cells (DC) in vivo is essential to the initiation of primary and secondary T cell responses. We have reported that DC presenting Ag in the context of MHC I molecules also become targets of specific CTL and are rapidly killed in mice. However, activated DC up-regulate expression of serine protease inhibitor (SPI)-6, a specific blocker of the cytotoxic granule protein granzyme B, which modulates their susceptibility to CTL-mediated killing in vitro. We wanted to determine whether susceptibility to CTL-mediated killing in vivo is also modulated by DC activation. As was previously reported by others, DC treated with different doses of LPS expressed higher levels of SPI-6 mRNA than did untreated DC. The increased expression of SPI-6 was functionally relevant, as LPS-treated DC became less susceptible to CTL-mediated killing in vitro. However, when these LPS-treated DC were injected in vivo, they remained sensitive to CTL-mediated killing regardless of whether the CTL activity was elicited in host mice via active immunization or was passively transferred via injection of in vitro-activated CTL. LPS-treated DC were also sensitive to killing in lymph node during the reactivation of memory CTL. We conclude that increased SPI-6 expression is not sufficient to confer DC with resistance to direct killing in vivo. However, SPI-6 expression may provide DC with a survival advantage in some conditions, such as those modeled by in vitro cytotoxicity assays.

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 funded by a research grant from the Royal Society of New Zealand Marsden Fund and the Health Research Council of New Zealand to F.R. H.S. was the recipient of a Lottery Health Ph.D. Scholarship, and R.P. was the recipient of a University of Otago Ph.D. Scholarship.

² Current address: Institute of Immunology, Medical University of Vienna, Lazarettgasse 19, 1090 Vienna, Austria.

³ Current address: Division of Haematology/Medical Oncology, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett Street, Victoria, Australia.

⁴ Address correspondence and reprint requests to Dr. Franca Ronchese, Malaghan Institute of Medical Research, P.O. Box 7060, Wellington, New Zealand. E-mail address: fronchese{at}malaghan.org.nz

⁵ Abbreviations used in this paper: DC, dendritic cells; BM-DC, bone marrow-derived DC; CTO, Cell Tracker Orange; gp33, fragment 33–41 of the lymphocytic choriomeningitis virus glycoprotein; SPI-6, serine protease inhibitor 6; SPI-CI, serine protease inhibitor involved in cytotoxicity inhibition.