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Cells Effects on the Activation and Apoptosis of T Induces Opposing Fibronectin-Associated Fas Ligand Rapidly Induces Opposing and Time-Dependent Effects on the Activation and Apoptosis of T Cells This information is current as of September 28, 2021. Alexandra Zanin-Zhorov, Rami Hershkoviz, Iris Hecht, Liora Cahalon and Ofer Lider J Immunol 2003; 171:5882-5889; ; doi: 10.4049/jimmunol.171.11.5882 http://www.jimmunol.org/content/171/11/5882 Downloaded from References This article cites 40 articles, 17 of which you can access for free at: http://www.jimmunol.org/content/171/11/5882.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Fibronectin-Associated Fas Ligand Rapidly Induces Opposing and Time-Dependent Effects on the Activation and Apoptosis of T Cells1 Alexandra Zanin-Zhorov, Rami Hershkoviz, Iris Hecht, Liora Cahalon, and Ofer Lider2 Recently, it has been shown that Fas ligand (FasL) interacts with the extracellular matrix (ECM) protein fibronectin (FN), and that the bound FasL retains its cytotoxic efficacy. Herein, we examined the ramifications of FasL-ECM protein interactions throughout a specific time period, in the absence or presence of additional activating molecules, assuming that these complexed interactions occur during inflammation. We found that exposure of purified human T cells to FN-associated recombinant FasL for ␤ as brief as 5–10 min at 0.1–100 ng/ml induced their adhesion in 1 integrin- and FasR-dependent manners while activating the intracellular protein kinase, Pyk-2. The FN-associated FasL stops the CXCL12 (stromal cell-derived factor 1␣)-induced chemo- Downloaded from taxis of T cells by inhibiting the chemokine-induced extracellular signal-regulated kinase signaling and cytoskeletal rearrange- ment. This short term exposure of T cells to the FN-bound FasL (1 ng/ml), which was followed by T cell activation via the CD3 complex, resulted in 1) increased secretion of IFN-␥ (measured after 24 h), and 2) enhanced T cell apoptosis (measured after 72 h). Thus, in the context of inflamed ECM and depending on the time after FasL activation, its concentration, and the nature of other contextual mediators, FasL initially retains effector T cells at sites of inflammation and, later, induces T cell apoptosis and return to homeostasis. The Journal of Immunology, 2003, 171: 5882–5889. http://www.jimmunol.org/ he functioning of immune cells, such as T cells, during coproteins of the ECM, and that such ECM-anchored FasL retains inflammation must be tightly controlled and time-limited. its cytotoxic potential (14). T These T cell functions depend on the existence of diverse We and other researchers have found that the ECM and, in par- inflammatory-modulating molecules, the cell’s state of activation, ticular, FN, can bind various growth factors, cytokines, and che- and the recognition of other collaborating cells and tissue compo- mokines and thereby affect immune cell activation and function in nents, including those of the extracellular matrix (ECM).3 One a site-restrictive manner (15–19). The ECM-anchored or associ- ␤ such mechanism that controls cell activation, function, and viabil- ated mediators affect monocyte and T cell activation, as well as 1 ity may be associated with the local interaction of T cells with Fas integrin functions associated with recognition of the surrounding by guest on September 28, 2021 ligand (FasL; CD95L). The engagement of stimulated T cells with tissue components, in addition to cell adhesion, migration, and cross-linked FasL leads to the activation of a caspase signaling cytokine and enzyme secretion (17, 20, 21). We have assumed that pathway that culminates in activation-induced apoptosis (1, 2). although the ECM-associated FasL can ultimately signal T cell However, in addition to its proapoptotic effects, it is now becoming death upon activation, in the short term it can also affect the proin- evident that FasL can function as an immune cell-activating factor flammatory functions of these cells. Based on our results, we pos- (3–6). Fas activation leads to T cell and neutrophil proliferation tulate that within the ECM, and depending on the time kinetics of (7), cytokine secretion (8, 9), angiogenesis and endothelial cell the interactions and the presence of other activatory moieties, FasL proliferation (9), and an increase in integrin expression on epithe- may differentially affect the activatory behavior of T cells and their lial cells (10). Although soluble FasL do not signal cell death (1, death and, consequently, the duration and intensity of the inflam- 2), it induces the chemotaxis of neutrophils (11, 12) and reduces matory reaction. neutrophil adhesion to endothelial cells (13). FasL can function in the context of the ECM; it has been found that FasL binds fi- Materials and Methods bronectin (FN) and vitronectin, two prototypic cell-adhesive gly- Reagents The following reagents and chemicals were purchased from the sources indicated: RPMI 1640 (Life Technologies, Paisley, U.K.); FCS, HEPES Department of Immunology, Weizmann Institute of Science, Rehovot, Israel buffer, antibiotics, and sodium pyruvate (Kibbutz Beit-Haemek, Israel); Received for publication July 2, 2003. Accepted for publication September 25, 2003. collagen type I (CO-I; Cellagen, ICN Pharmaceuticals, Costa Mesa, CA); The costs of publication of this article were defrayed in part by the payment of page collagen type VI (CO-IV; Sigma-Aldrich, Rehovot, Israel); FN (Chemicon, charges. This article must therefore be hereby marked advertisement in accordance Temecula, CA); laminin (LN); PMA, and the FN peptides, RGDS, RGES, with 18 U.S.C. Section 1734 solely to indicate this fact. and Leu-Asp-Val (LDV; Sigma-Aldrich). Recombinant human stromal ␣ ␣ 1 This work was supported by grants from the Minerva Foundation (Germany) and the cell-derived factor 1 (SDF-1 ), IL-2, soluble human extracellular FasL (a Israeli Science Foundation founded by the Israel Academy of Sciences and Human- monomeric 19.9-kDa protein, 175 aa residues), and TNF-␣ were purchased ities (Grant 1036/03). O.L. is the incumbent of the Weizmann League Career Devel- from PeproTech Asia (Rehovot, Israel). The ED50 of the cytotoxic effect of opment Chair in Children’s Diseases. this FasL is Ͻ10 ng/ml, corresponding to a sp. act. of Ͼ105 U/mg. mAbs ␤ 2 Address correspondence and reprint requests to Dr. Ofer Lider, Department of Im- directed against human 1 integrins (CD29, clone 3SS) and CD26 were munology, Weizmann Institute of Science, Rehovot 76100, Israel. E-mail address: obtained from Serotec (Oxford, U.K.). Neutralizing and activating mAb [email protected] against FasL and FasR, clones ZB4 and CH-11, respectively, were pur- 3 Abbreviations used in this paper: ECM, extracellular matrix; CO, collagen; ERK, chased from MBL (Nagoya, Japan). Capturing mAb anti-FasL (clone 4A5) extracellular signal-regulated kinase; FN, fibronectin; LDV, Leu-Asp-Val; LN, lami- and biotin-labeled mAb anti-FasL (clone 4H9) were purchased from MBL nin; PI3-K, phosphoinositol 3-kinase; PI-RGD, Arg-Gly-Asp; PKC, protein kinase C; (Nagoya, Japan). Polyclonal Ab against phosphorylated Pyk2 (clone SDF-1␣, stromal cell-derived factor 1␣. py881) was obtained from BioSource (Camarillo, CA), anti-total Pyk2 Copyright © 2003 by The American Association of Immunologists, Inc. 0022-1767/03/$02.00 The Journal of Immunology 5883 (clone N-19) was obtained from Santa Cruz Biotechnology (Santa Cruz, buffer was then added, and after boiling, the samples, containing equal CA), polyclonal Ab against phosphorylated extracellular signal-regulated amounts of proteins, were separated on 10% SDS-PAGE gel and trans- kinase2 (ERK2) was obtained from BioSource, anti-total ERK2 was ob- ferred to nitrocellulose membranes. The nitrocellulose membranes were tained from Sigma-Aldrich, and anti-human CXCR4 (clone 44708.111) blocked with TBST (20 mM Tris, 135 mM NaCl2, and 0.1 Tween 20, pH and anti-human CCR7 (clone 6B3) were purchased from R&D Systems 7.5) containing 5% low fat milk and probed with the following mAb in (Minneapolis, MN) and MBL (Nagoya, Japan), respectively. Inhibitors of blocking buffer: anti-phosphorylated Pyk2 (1.5 ␮g/ml), anti-total Pyk2 (0.2 intracellular signal transduction pathways, namely wortmanin and ␮g/ml), anti-phosphorylated ERK (0.2 ␮g/ml), or anti-total ERK (1/20,000 LY294002 (phosphoinositol 3-kinase (PI3-K) inhibitors), GF109203X from stock). Immunoreactive protein bands were visualized using a HRP- (protein kinase C (PKC) inhibitor), and pertussis toxin (G protein inhibitor) conjugated secondary Ab and the ECL system (20, 21). were obtained from Calbiochem (San Diego, CA). Actin polymerization Human T cells ϫ 6 o T cells (3 10 cells/ml) were preincubated with FasL (1 h, 37 C, 7% CO2 T cells were purified from healthy human donor peripheral blood. The humidified atmosphere) and treated with 500 ng/ml of SDF-1␣ for 15 s at o whole blood was incubated with RosetteSep human T cell enrichment 37 C and then fixed by the addition of a 3-fold volume of 3.7% PFA for o cocktail (StemCell Technologies, Vancouver, Canada) for 20 min at 22°C. 10 min at 22 C.
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