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Activation Cell Homeostasis in Chronic Immune Cutting Edge Cutting Edge: CD95 Maintains Effector T Cell Homeostasis in Chronic Immune Activation This information is current as Ramon Arens, Paul A. Baars, Margot Jak, Kiki Tesselaar, of September 24, 2021. Martin van der Valk, Marinus H. J. van Oers and René A. W. van Lier J Immunol 2005; 174:5915-5920; ; doi: 10.4049/jimmunol.174.10.5915 http://www.jimmunol.org/content/174/10/5915 Downloaded from References This article cites 30 articles, 9 of which you can access for free at: http://www.jimmunol.org/content/174/10/5915.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 24, 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 © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. THE JOURNAL OF IMMUNOLOGY CUTTING EDGE Cutting Edge: CD95 Maintains Effector T Cell Homeostasis in Chronic Immune Activation Ramon Arens,1*†‡ Paul A. Baars,* Margot Jak,* Kiki Tesselaar,* Martin van der Valk,§ Marinus H. J. van Oers,† and Rene´A. W. van Lier1* The elimination of activated T cells is important to main- reports suggested that the death of primed T cells in vivo is tain homeostasis and avoid immunopathology. CD95 independent from the CD95 system (10–13). (Fas/APO-1) has been identified as a death mediator for TNFR-associated factor (TRAF)2 binding TNFR family activated T cells in vitro but the function of CD95 in members, such as OX40, 4–1BB, and CD27, influence T cell death of mature T cells in vivo is still controversial. Here division, survival, and effector function (14). These receptors we show that triggering of the costimulatory TNF receptor can antagonize mitochondrion-dependent cell death by up-reg- Downloaded from family member CD27 sensitized T cells for CD95-in- ulating anti-apoptotic Bcl-2 family molecules such as Bcl-xL duced apoptosis. CD95-deficient (lpr/lpr) T cells mas- and Bfl (Refs. 15 and 16 and unpublished data). sively expanded and differentiated into IFN-␥-secreting In the present study, we questioned whether CD95-induced effector cells in transgenic mice that constitutively express cell death has a role in the regulation of expansion of T cells stimulated via CD27. Whereas previous reports showed that the CD27 ligand, CD70. Concomitantly, CD95-defi- http://www.jimmunol.org/ CD27 stimulation enhanced the magnitude of T cell responses cient CD70 transgenic mice became moribund by 4 wk of (17, 18), we here found that CD27-CD70 interaction sensitizes age with severe liver pathology and bone marrow failure. T cells for CD95-mediated apoptosis, thereby providing evi- These findings establish that CD95 is a critical regulator dence for an in-built feedback mechanism. Thus, CD27-CD70 of effector T cell homeostasis in chronic immune interactions can operate as a double-edged sword by either in- activation. The Journal of Immunology, 2005, 174: ducing T cell survival while increasing sensitivity to death by 5915–5920. CD95. fter initial clonal expansion in response to Ag most of Materials and Methods by guest on September 24, 2021 the responding T cells die by apoptosis and only few Mice Ag-specific T cells are preserved as memory T cells. Ϫ Ϫ A The mice strains used were C57BL/6, CD70 Tg (21), CD27 / (17), F5 TCR The death of the activated T cells is important to maintain ho- Tg (30) (kindly provided by Dr. D. Kioussis, National Institute for Medical meostasis and avoid immunopathology generated by toxic side Research, London, U.K.), IFN-␥Ϫ/Ϫ, and lpr/lpr mice (purchased from The effects of effector T cell molecules (1). Jackson Laboratory). All mice strains are on a C57BL/6 background. CD70 Tg mice were crossed with CD27Ϫ/Ϫ, F5 TCR Tg, lpr/lpr, and IFN-␥Ϫ/Ϫ mice. All Signaling through members of the death domain contain- mice were bred in the animal facility of The Netherlands Cancer Institute (Am- ing TNF receptor (TNFR) family such as CD95, TNFR1, sterdam) under specific pathogen-free conditions and were handled in accor- and DR4/5 induces apoptosis by the recruitment of a signal dance with institutional and national guidelines. CD27Ϫ/Ϫ, IFN-␥Ϫ/Ϫ, and transduction complex that activates caspase enzymes (2). Ac- lpr/lpr mutant mice were genotyped by PCR analysis of tail DNA. CD70 Tg and F5 TCR Tg mice were genotyped by FACS analysis using CD70 mAb and tive caspases induce cleavage of structural and regulatory V␤11 mAb, respectively. proteins within cells and leads ultimately to apoptosis. Hu- mans and mice with mutations in the genes encoding for ei- Cell preparation and flow cytometry ther CD95 or its ligand progressively accumulate lympho- Single cell suspensions were prepared from freshly isolated spleens, lymph cytes in the periphery and are susceptible to develop nodes (axillary, brachial, inguinal, and mesenteric), and thymus by mincing and autoimmune diseases (2). In vitro CD95 was identified as an gently pressing the tissues through cell strainers. Bone marrow (femurs and tib- essential mediator of apoptosis for activated T cells (3–5). ias) single cell suspensions were prepared by flushing the bones with a needle. Subsequent studies using mice deficient in CD95 (lpr mice) Erythrocytes were lysed with ammonium chloride buffer. Surface staining and intracellular staining for cell surface molecules and cytokines was performed as or CD95 ligand (gld mice) showed that CD95-CD95L in- described (21) using Abs to CD4, CD8, CD62L, CD44, CD45R/B220, CD43 teractions regulate T cell homeostasis (6–9). However, other (clone 1B11), CD95, IL-2, TNF, IFN-␥, and IL-10 (BD Pharmingen). Flow Departments of *Experimental Immunology and †Hematology, Academic Medical Cen- 1 Address correspondence and reprint requests to Dr. Ramon Arens or Dr. Rene´A.W.van ter, University of Amsterdam, Amsterdam, The Netherlands; ‡Department of Immunol- Lier, Department of Experimental Immunology, Academic Medical Center, University of ogy and §Laboratory of Experimental Animal Pathology, The Netherlands Cancer Insti- Amsterdam, P.O. Box 22700, 1100 DD Amsterdam, The Netherlands. E-mail addresses: tute, Amsterdam, The Netherlands [email protected] and [email protected], respectively. Received for publication February 9, 2005. Accepted for publication March 7, 2005. 2 Abbreviations used in this paper: TRAF, TNFR-associated factor; Tg, transgenic; LN, lymph nodes. 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. Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 5916 CUTTING EDGE: REQUIREMENT OF CD95 IN CHRONIC T CELL ACTIVATION cytometric analysis was performed on a FACSCalibur with Cell Quest software benzidine substrate for visualization. After counterstaining with hematoxylin, (BD Biosciences). slides were mounted. For negative control, the primary mAb was omitted. Lymphocyte purification Results and Discussion To purify wild-type T cells, lymph node cell suspensions from 6- to 8-wk-old CD27 stimulation sensitizes T cells for CD95-mediated apoptosis wild-type mice were incubated with rat-anti-mouse MHC class II and rat-anti- mouse B220 Abs for 30 min at 4°C, washed and incubated with goat-anti-rat We first tested whether CD27 stimulation by its ligand CD70 IgG microbeads (Miltenyi Biotec) for 20 min at 4°C. After washing, cells were influenced CD95 cell surface expression on T cells and/or mod- magnetically separated with the MACS (negative selection T cells). To purify B cells, splenic cell suspensions from CD70 Tg and CD27Ϫ/Ϫ mice were incu- ulated susceptibility to CD95-induced apoptosis. CD3-stimu- bated with mouse CD19 microbeads (Miltenyi Biotec) for 20 min at 4°C. After lated wild-type T cells were cultured in the presence or absence washing, cells were magnetically separated with the MACS (positive selection B of CD27 stimulation by the addition of CD70 transgenic (Tg) cells). The T and B cell fractions were consistently found to be Ͼ95% CD3ϩ ϩ or control B cells, respectively. CD95 expression on T cells in- and Ͼ95% B220 , respectively, as evidenced by flow cytometry. creased with CD27 stimulation (Fig. 1A). Moreover, an in- T cell activation, CD95 expression, and CD95-mediated apoptosis assay creased proportion of the CD3/CD27 stimulated T cells un- T cells (1 ϫ 106 cells/ml) were stimulated with 1 ␮g/ml coated CD3 mAb derwent CD95-induced apoptosis compared with CD3 (purified from hybridoma supernatants, clone CRL 1975) and cultured 1:1 treatment alone (Fig. 1B), indicating that CD70 sensitizes T Ϫ Ϫ Ϫ Ϫ with either purified CD27 / ϫ CD70 Tg B cells or purified CD27 / B cells cells for CD95-mediated apoptosis in vitro. To test CD95 sus- in IMDM medium containing 10% FCS. CD95 expression on T cells was an- alyzed after 24 h by flow cytometry with PE-conjugated anti-CD95 mAb (clone ceptibility in vivo, we adoptively transferred influenza-specific Jo2; BD Pharmingen) and allophycocyanin-conjugated antiCD3 mAb (BD TCR Tg T cells and CD95-deficient (lpr/lpr) influenza-specific Downloaded from Ϫ Ϫ Ϫ Ϫ Pharmingen).
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