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CC Chemokine Ligand 25 Enhances Resistance to Apoptosis in CD4 T

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CC Chemokine Ligand 25 Enhances Resistance to Apoptosis in CD4 T [CANCER RESEARCH 64, 7579–7587, October 15, 2004] CC Chemokine Ligand 25 Enhances Resistance to Apoptosis in CD4؉ T Cells from Patients with T-Cell Lineage Acute and Chronic Lymphocytic Leukemia by Means of Livin Activation Zhang Qiuping,1 Xiong Jei,1,2 Jin Youxin,2 Ju Wei,1 Liu Chun,1 Wang Jin,1 Wu Qun,1 Liu Yan,1 Hu Chunsong,3 Yang Mingzhen,4 Gao Qingping,5 Zhang Kejian,5 Sun Zhimin,6 Li Qun,3 Liu Junyan,1 and Tan Jinquan1,3 1Department of Immunology, and Laboratory of Allergy and Clinical Immunology, Institute of Allergy and Immune-related Diseases and Center for Medical Research, Wuhan University School of Medicine, Wuhan; 2The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai; 3Department of Immunology, College of Basic Medical Sciences, Anhui Medical University, Hefei; 4Department of Hematology, The Affiliated University Hospital, Anhui Medical University, Hefei; 5Department of Hematology, The First and Second Affiliated University Hospital, Wuhan University, Wuhan; and 6Department of Hematology, The Provincial Hospital of Anhui, Hefei, Peoples Republic of China ABSTRACT intestine (8), providing the evidence for distinctive mechanisms of -؉ lymphocyte recruitment. The importance of CCL25/TECK is to li We investigated CD4 and CD8 double-positive thymocytes, CD4 T cense effector/memory cells to access anatomic sites (9, 10). Thus, cells from typical patients with T-cell lineage acute lymphocytic leukemia CCL25/TECK is important for the homing, development, and home- (T-ALL) and T cell lineage chronic lymphocytic leukemia (T-CLL), and MOLT4 T cells in terms of CC chemokine ligand 25 (CCL25) functions of ostasis of T cells, particularly, mucosal T cells. The functional im- induction of resistance to tumor necrosis factor ␣ (TNF-␣)–mediated portance of CCR9/CCL25 in the physiologic and pathophysiologic apoptosis. We found that CCL25 selectively enhanced resistance to TNF- events of T-cell trafficking and selection is not fully understood .mediated apoptosis in T-ALL and T-CLL CD4؉ T cells as well as in despite a considerable body of investigations–␣ MOLT4 T cells, but CD4 and CD8 double-positive thymocytes did not. The inhibitor of apoptosis protein (IAP) family plays a key role in One member protein of the inhibitor of apoptosis protein (IAP) family, apoptosis regulation and has become increasingly prominent in the Livin, was selectively expressed in the malignant cells at higher levels, field of cancer (11). Thus far, eight human IAPs have been identified: ؉ particularly in T-ALL CD4 T cells, in comparison with the expression in c-IAP1, c-IAP2, NAIP, survivin, XIAP, Bruce, ILP-2, and Livin (11). CD4 and CD8 double-positive thymocytes. After stimulation with CCL25 IAPs can block apoptosis mainly through their ability to bind and and apoptotic induction with TNF-␣, the expression levels of Livin in these inhibit specific caspases such as caspase-3 and -7 (12, 13). A novel malignant cells were significantly increased. CCL25/thymus-expressed chemokine (TECK), by means of CC chemokine receptor 9 (CCR9) IAP member, designated Livin/ML-IAP/KIAP (14, 15), is suggested ligation, selectively activated Livin to enhance resistance to TNF-␣– to mediate suppression of cell death (14–16). A key function for Livin in the transformed phenotype suggests that this protein may be an mediated apoptosis in c-jun-NH2-kinase 1 (JNK1) kinase-dependent man- ner. These findings suggested differential functions of CCR9/CCL25 in important target for immune-mediated tumor destruction (17). distinct types of cells. CD4 and CD8 double-positive thymocytes used A common manifestation of T-cell lineage acute lymphocytic leu- CCR9/CCL25 for migration, homing, development, maturation, selection, kemia (T-ALL) and T-cell lineage chronic lymphocytic leukemia ؉ cell homeostasis, whereas malignant cells, particularly T-ALL CD4 T (T-CLL) is infiltration of various organs by leukemic cells (18). We cells, used CCR9/CCL25 for infiltration, resistance to apoptosis, and have reported that CCR9 is selectively and functionally overexpressed inappropriate proliferation. on T-ALL and T-CLL CD4ϩ T cells (19). Despite these findings, little is known about the exact mechanisms and molecule regulation in the homing, migration, inappropriate proliferation, and resistance to apo- INTRODUCTION ptosis of T-ALL and T-CLL T cells. CC chemokine ligand 25 (CCL25), also known as thymus-ex- pressed chemokine (TECK), together with CC chemokine receptor 9 (CCR9), efficaciously induces chemotaxis of immature CD4ϩCD8ϩ MATERIALS AND METHODS double-positive, and mature CD4ϩ and CD8ϩ single-positive thymo- Patients and Cell Purification. All of the patients with T-ALL and T-CLL cytes, suggesting that CCL25/CCR9 interaction plays a pivotal role in were diagnosed according to The French-American-British (FAB) Cooperative T-cell migration in the thymus (1–4). CCL25/TECK delivers signals Group criteria (20) and to the guidelines of the National Cancer Institute through CCR9 for developing of thymocytes (5), and developing Working Group on B-CLL (21, 22), and informed consent according to Ϫ Ϫ and/or migrating of both ␣␤ and ␥␦ T cells (6). CCR9 activation institutional guidelines. CD4ϩ T cells were purified by a positive selection leads to phosphorylation of glycogen synthase kinase-3␤ (GSK-3␤) procedure of Dynabeads (Dynal A/S, Dynal, Norway). The malignancy of and forkhead transcriptional factor (FKHR) and provides a cell- purified T-ALL or T-CLL CD4ϩ T cells was checked by expression of CD25, survival signal (7). In the normal human, CCR9 is restrictedly ex- CD45RO, and HLA-DR (19). Human thymus tissue was aseptically obtained pressed at high levels on CD4ϩ and CD8ϩ T cells in the small after consent during surgical operative procedures involving the mediastinal region. Stromal cells were prepared by enzymatic digestion of thymus tissue, as described previously (23). CD4 and CD8 double-positive thymocytes were Received 2/21/04; revised 7/19/04; accepted 8/19/04. sorted with a FACSstarPlus. The cell lines were obtained from the American Grant support: This work was supported by the National Science Foundation of China (no. 39870674), Science Foundation of Anhui Province, China (no. 98436630), and Type Culture Collection, Manassas, VA (MOLT4 and human embryonic Education and Research Foundation of Anhui Province, China (no. 98JL063) and Re- kidney cells 293T). The anti-CCR9 monoclonal antibody and chemokines search Foundation from Health Department of Hubei Provincial Government, China (no. (CCL25/TECK, CXC (CC) chemokine ligand 12 (CXCL12)/SDF-1) were 301140344). purchased from R&D Systems, Abingdon, United Kingdom. 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 Flow Cytometry. For detection of apoptosis, cells were stained in staining 18 U.S.C. Section 1734 solely to indicate this fact. buffer with 1 ␮g/mL propidium iodide for 30 minutes at 4°C, then stained with Note: Z. Qiuping and X. Jei contributed equally to this work. FITC-conjugated annexin V with binding buffer (BD PharMingen, San Diego, Requests for reprints: Tan Jinquan, Department of Immunology, Wuhan University CA) as described previously (7, 24). COULTER XL (Coulter, Miami, FL) was School of Medicine, Dong Hu Road 115, Wuchang 430071, Wuhan, Peoples Republic of China; Phone: 86-27-87331681; Fax: 45-35365326; E-mail: [email protected]. used for analyses. For detection of intracellular active caspases, cytofix/ ©2004 American Association for Cancer Research. cytoperm buffer (BD PharMingen) was used to permeabilize cells, and cells 7579 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2004 American Association for Cancer Research. APOPTOTIC RESISTANCE VIA CCR9/LIVIN/JNK1 PATHWAY were subsequently stained with anti-active-capsase-3 or anti-active-caspase-8 under constant agitation. Immune complexes were allowed to bind to 20 ␮Lof monoclonal antibody (BD PharMingen). Data were analyzed by means of the protein A-Sepharose beads overnight, beads were washed three times with WinList program (The Scripps Research Institute, La Jolla, CA). lysis buffer, then suspended in 20 ␮L of kinase buffer containing 10 ␮Ci of Real-time Quantitative Reverse Transcription-PCR Assay. All real- [␥-32P]ATP and were incubated at 30°C for 30 minutes. The reaction was time quantitative reverse transcription-PCR (RT-PCR) reactions were done as stopped by the addition of 15 ␮Lof3ϫ sample buffer. Immunoprecipitates described elsewhere (24–26). Briefly, total RNA from purified cells (1 ϫ 105, were separated on SDS-12% polyacrylamide gels and were transferred to purity Ͼ99%) was prepared by using Quick Prep total RNA extraction kit nitrocellulose membranes. Filters were blocked with 5% nonfat milk in block- (Pharmacia Biotech, Hillerød, Denmark). RNA was reverse transcribed by ing buffer and were incubated with specified antibody for 2 hours, followed by using oligo(dT)12–18 and Superscript II reverse transcriptase (Life Technolo- autoradiography. gies, Inc., Grand Island, NY). The real-time quantitative PCR was performed Chemotaxis Assay. The chemotaxis assay was performed in a 48-transwell with an ABI PRISM 7700 Sequence Detector Systems (Applied Biosystems, microchamber (Neuro Probe, Bethesda, MD) technique (7, 19). Briefly, che- Foster City, CA). By using SYBR Green PCR Core Reagents kit,
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