Expression of the Serpin Serine Protease Inhibitor 6 Protects Dendritic Cells from Cytotoxic T Lymphocyte-induced Apoptosis: Differential Modulation by T Helper Type 1 and Type 2 Cells

doi:10.1084/jem.194.5.657

Published online 4 September 2001. doi:10.1084/jem.194.5.657

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© The Rockefeller University Press, 0022-1007/2001/9/657/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 5, September 3, 2001 657-668

Original Article

Expression of the Serpin Serine Protease Inhibitor 6 Protects Dendritic Cells from Cytotoxic T Lymphocyte–induced Apoptosis: Differential Modulation by T Helper Type 1 and Type 2 Cells

Jan Paul Medema^a, Danita H. Schuurhuis^a, Delphine Rea^a, Joost van Tongeren^a, Joan de Jong^a, Sandra A. Bres^a, Sandra Laban^a, René E.M. Toes^a, Mireille Toebes^c, Ton N.M. Schumacher^c, Bellinda A. Bladergroen^b, Ferry Ossendorp^a, J. Alain Kummer^b, Cornelis J.M. Melief^a, and Rienk Offringa^a
^a Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), 2333ZA Leiden, Netherlands
^b Department of Pathology, Free University Hospital, 1007 MB Amsterdam, Netherlands
^c Division of Immunology, Netherlands Cancer Institute, 1066CX Amsterdam, Netherlands

Correspondence to: Jan Paul Medema, Dept. of Immunohematology and Blood Transfusion, LUMC, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Tel:00-31-71-5263013 Fax:00-31-71-5216751 E-mail:medema{at}mail.medfac.leidenuniv.nl.

Dendritic cells (DCs) play a central role in the immune systemas they drive activation of T lymphocytes by cognate interactions.However, as DCs express high levels of major histocompatibilitycomplex class I, this intimate contact may also result in eliminationof DCs by activated cytotoxic T lymphocytes (CTLs) and therebylimit induction of immunity. We show here that immature DCsare indeed susceptible to CTL-induced killing, but become resistantupon maturation with anti-CD40 or lipopolysaccharide. Protectionis achieved by expression of serine protease inhibitor (SPI)-6,a member of the serpin family that specifically inactivatesgranzyme B and thereby blocks CTL-induced apoptosis. Anti-CD40and LPS-induced SPI-6 expression is sustained for long periodsof time, suggesting a role for SPI-6 in the longevity of DCs.Importantly, T helper 1 cells, which mature DCs and boost CTLimmunity, induce SPI-6 expression and subsequent DC resistance.In contrast, T helper 2 cells neither induce SPI-6 nor conveyprotection, despite the fact that they trigger DC maturationwith comparable efficiency. Our data identify SPI-6 as a novelmarker for DC function, which protects DCs against CTL-inducedapoptosis.

Key Words: granzyme, CTL, survival, CD40, LPS

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