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Cells and at Immune-Privileged Sites Dendritic Inhibitor 9, Is Mainly The Granzyme B Inhibitor, Protease Inhibitor 9, Is Mainly Expressed by Dendritic Cells and at Immune-Privileged Sites1 Bellinda A. Bladergroen,* Merel C. M. Strik,† Niels Bovenschen,* Oskar van Berkum,* George L. Scheffer,* Chris J. L. M. Meijer,* C. Erik Hack,†‡ and J. Alain Kummer2* Granzyme B is released from CTLs and NK cells and an important mediator of CTL/NK-induced apoptosis in target cells. The human intracellular serpin proteinase inhibitor (PI)9 is the only human protein able to inhibit the activity of granzyme B. As a first step to elucidate the physiological role of PI9, PI9 protein expression in various human tissues was studied. A mAb directed against human PI9 was developed, which specifically stained PI9-transfected COS-7 cells, and was used for immunohistochem- istry. Both in primary lymphoid organs and in inflammatory infiltrates, PI9 was present in different subsets of dendritic cells. Also T-lymphocytes in primary and organ-associated lymphoid tissues were PI9 positive. Endothelial cells of small vessels in most organs tested as well as the endothelial layer of large veins and arteries showed strong PI9 staining. Surprisingly, high PI9 protein expression was also found at immune-privileged sites like the placenta, the testis, the ovary, and the eye. These data fit with the hypothesis that PI9 is expressed at sites where degranulation of CTL or NK cells is potentially deleterious. The Journal of Immunology, 2001, 166: 0000–0000. ytotoxic cells such as NK cells and CTL form an impor- phocytes, and Fas-associated death domain-like IL-1-converting tant line of defense against virally infected cells and tu- enzyme-inhibitory protein (3), which directly inhibits the Fas-me- C mor cells. CTL and NK cells kill target cells by inducing diated signaling pathway (6). Fas ligand is expressed by target apoptosis in the latter. This mainly occurs via two pathways, one cells in immune-privileged sites like testis and the eye (7, 8). involving the death receptor induced apoptosis (mainly the Fas As the apoptotic machinery is mediated by activation of a cas- ligand/Fas pathway), the other being dependent on the exocytosis cade of proteases, cells could also escape apoptosis by expressing of cytotoxic granules from the effector cell. Cytotoxic granules intracellular protease inhibitors. Indeed, inhibition of apoptosis has contain perforin, which forms pores in the membrane of the target been shown for the poxvirus serine protease inhibitor (serpin) cell, and several serine proteases, termed granzymes. Studies with crmA, which mainly inhibits caspase 1, but may also inhibit Fas- purified components (1), transfected cells (2), and knock-out mice mediated apoptosis by inhibition of caspase 8 (reviewed in Ref. 9). (3, 4) have established perforin to be essential for membrane lysis, Furthermore, the human intracellular serpin plasminogen activator and granzyme B to be necessary for rapid target cell DNA frag- inhibitor 2 (PAI-2)3 can protect cells from TNF-induced apoptosis mentation and apoptosis. The signaling pathway involving Fas li- (10). CrmA and PAI-2 both belong to the subfamily of OVA ser- gand and Fas is an important complementary route, as evidenced pins that are usually present as intracellular cytoplasmic proteins by the residual, slow cytotoxic activity in perforin-deficient mice, (9). The function of these serpins is largely unknown. Recently, a which is abrogated using target cells from Fas-deficient lpr/lpr novel human intracellular serpin, proteinase inhibitor (PI) 9, was mice (5). Importantly, the granzyme B- as well as Fas-mediated described to be expressed by CTLs. This serpin efficiently inhibits apoptosis is finally executed by unique cysteine proteases granzyme B in vitro and in vivo and, hence, PI9 transfected cells (caspases). Granzyme B shares its unusual substrate specificity are protected against granzyme B mediated apoptosis (11, 12). with these caspases. Consequently, this mediator of cytotoxicity Using RT-PCR and Northern blotting it was shown that PI9 can directly trigger the endogenous apoptotic machinery. mRNA is mainly expressed by B and T cell lines and, therefore, it Recent studies indicate that normal and pathological cells can was proposed that PI9 protects CTLs against death induced by protect themselves against apoptotic stimuli at different levels. their own misdirected granzyme B (11). Cells of the immune system as well as certain tumor cells can At the moment PI9 is the only human inhibitor known to inter- express several proteins that confer resistance to Fas-mediated ap- fere with granzyme B mediated apoptosis. As a first step to resolve optosis, such as Fas ligand, which kills attacking cytotoxic lym- the (patho)physiological function of this inhibitor, we decided to study the expression of this inhibitor in various human tissues. Departments of *Pathology and †Clinical Chemistry, Free University Hospital, Am- sterdam, the Netherlands; and ‡Department of Pathophysiology of Plasma Proteins, Materials and Methods Central Laboratory of The Netherlands Red Cross Blood Transfusion Service, Am- sterdam, The Netherlands Materials and cells Received for publication August 9, 2000. Accepted for publication December COS-7 cells (CRL-1651; American Type Culture Collection, Manassas, 11, 2000. VA) were described in Ref. 13. YT-Indy cells were kindly provided by Dr. The costs of publication of this article were defrayed in part by the payment of page C.J. Froelich (Department of Research, Evanston Hospital, Northwestern charges. This article must therefore be hereby marked advertisement in accordance University, Evanston, IL). DMEM and IMDM were obtained from Bio- with 18 U.S.C. Section 1734 solely to indicate this fact. Whittaker Europe (Verviers, Belgium). FBS was purchased from Life 1 This study was supported by the Dutch Cancer Foundation (Grant VU-98-1718). 2 Address correspondence and reprint requests to Dr. J. Alain Kummer, Department of Pathology, Free University Hospital, P.O. Box 7057, 1007 MB Amsterdam, The 3 Abbreviations used in this paper: PAI-2, plasminogen activator inhibitor 2; PI, pro- Netherlands. E-mail address: [email protected] teinase inhibitor; sABC, avidine-biotine-HRP complex. Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 The Journal of Immunology 3219 Technologies (Rockville, MD). All primers were synthesized by Eurogen- bodies, containing the rPI9, were pelleted by centrifugation at 14,000 rpm tec (Brussels, Belgium). Qiaex II Gel Extraction Kit and Qiagen Plasmid for 15 min and washed twice with 0.5% (w/v) Triton X-100 in TE buffer. Maxi Kit were obtained from Qiagen (Hilden, Germany). The pCR-Script Purified rPI9 inclusion bodies were resuspended in PBS to a final concen- Amp SKϩ cloning vector was obtained from Stratagene (La Jolla, CA) and tration of ϳ1 mg/ml, shortly sonicated, and used for immunization. pcDNA3.1/Hygroϩ from Invitrogen (Carlsbad, CA). Epicurian Coli XL1- Blue MRF’Kan super competent cells were obtained from Stratagene, and Production and purification of anti-PI9 mAbs JM109 high efficiency competent cells were obtained from Promega (Mad- Female BALB/c mice were immunized both s.c. and in the footpads ison, WI). The Thermo Sequenase DNA sequencing kit was purchased with 50 ␮g of purified rPI9 inclusion bodies suspended in CFA. This from Amersham (Arlington Heights, IL). mAb GB7 (subtype IgG2a) rec- was followed by one or two subsequent booster injections of 50 ␮g ognizing granzyme B was produced and purified as described previously inclusion bodies suspended in IFA at 10-day intervals. Three days after (14). Anti-CD21 mAb 1F8 (subtype IgG1), anti-S100 polyclonal Ab, bi- the last booster injection, popliteal lymph nodes were collected. Lym- Ј otinylated rabbit-anti-mouse F(ab )2 Ig, biotinylated swine-anti-rabbit phocytes were isolated and fused with mouse Sp2/0 myeloma cells as Ј F(ab )2, HRP-conjugated rabbit-anti-mouse Ig, avidine-biotine-HRP com- described previously (16). Hybridomas producing immunoreactive anti- plex (sABC), biotinylated tyramine, and streptavidine-FITC were obtained PI9 mAbs were identified by screening culture medium of the hybrid- from Dako (Glostrup, Denmark). Biotin-labeled goat-anti-mouse IgG1 and omas with ELISA on immobilized, rPI9 containing bacterial E. coli HRP-labeled goat-anti-mouse IgG2a Abs were obtained from Southern BL21 (DE3)pLysE lysate. Selected anti-PI9-producing hybridomas Biotechnology Associates (Birmingham, AL) and tyramine-rhodamine were subcloned by three cycles of limiting dilution. Anti-PI9 mAbs from DuPont Pharmaceuticals (Wilmington, DE). The constructs PI6- were purified from conditioned medium by protein A-Sepharose affinity pcDNA3 and PI8-pcDNA3 were a kind gift from Dr. W. Kisiel (Depart- chromatography. ment of Pathology, University of New Mexico, Albuquerque, NM). PAI- 2-pCI-neo was kindly provided by Dr. E.K. Kruithof (Division of Immunohisto/cytochemistry Angiology and Hemostasis, University Hospital Geneva, Geneva, Switzer- land). FuGENE 6 transfection reagent was obtained from Roche Molecular Slides with sections of formalin-fixed, paraffin-embedded normal human Biochemicals (Indianapolis, IN). 4-(2-aminoethyl)-benzenesulfonylfluo- tissues were obtained from the tissue bank of the Department of Pathology ride.HCl was obtained from A.G. Scientific (San Diego, CA) and apo- at the Free University Hospital (Amsterdam, the Netherlands). All tissues transferrine from Sigma (St. Louis, MO). The Micro BCA Protein Assay were sampled from surgical specimens within2hofresection. Tissues was obtained from Pierce (Rockford, IL). were processed routinely by fixation in 10% formalin for 18 h and subse- quently embedded in paraffin. Three-micrometer thick sections were Cell culture mounted on poly-L-lysine-coated slides. Cytospins of serpin-transfected COS-7 cells (see below) were fixed in 10% formalin for 1 h. COS-7 cells were grown in DMEM supplemented with 10% (v/v) heat- Endogenous peroxidase activity was blocked by incubation for 30 min inactivated FBS, 2 mM L-glutamine and penicillin/streptomycin at final with 0.3% (v/v) H2O2 in methanol. Unless stated otherwise, tissue sections concentrations of 50 IU/ml and 50 ␮g/ml, respectively.
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