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CCL2 Inhibits the Apoptosis Program Induced by Growth Factor Deprivation, Rescuing Functional T Cells1

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CCL2 Inhibits the Apoptosis Program Induced by Growth Factor Deprivation, Rescuing Functional T Cells1 The Journal of Immunology CCL2 Inhibits the Apoptosis Program Induced by Growth Factor Deprivation, Rescuing Functional T Cells1 Eva Diaz-Guerra,2 Rolando Vernal,2 M. Julieta del Prete,2 Augusto Silva, and Jose A. Garcia-Sanz3 The precise mechanisms involved in the switch between the clonal expansion and contraction phases of a CD8؉ T cell response remain to be fully elucidated. One of the mechanisms implicated in the contraction phase is cytokine deprivation, which triggers apoptosis in these cells. CCR2 chemokine receptor is up-regulated following IL-2 deprivation, and its ligand CCL2 plays an essential role preventing apoptosis induced by IL-2 withdrawal not only in CTLL2 cells, but also in mouse Ag-activated primary CD8؉ T cells because it rescued functional CD8؉ T cells from deprivation induced apoptosis, promoting proliferation in response to subsequent addition of IL-2 or to secondary antigenic challenges. Thus, up-regulation of the CCR2 upon growth factor with- drawal together with the protective effects of CCL2, represent a double-edged survival strategy, protecting cells from apoptosis and enabling them to migrate toward sites where Ag and/or growth factors are available. The Journal of Immunology, 2007, 179: 7352–7357. espite the continuous generation of T lymphocytes in the is induced by TCR stimulation of naive T cells in the absence of body, their total number is tightly regulated, implying costimulatory signals. Such T cell death can be inhibited in vivo by D that T cells disappear at about the same rate as they are inflammation and in vitro by cytokines; bacterial products promote being produced. During the course of an in vivo acute viral infec- T cell survival by a mechanism involving Bcl-3 (11). The second tion, the appropriate Ag presentation by APCs leads to a rapid is induced by repeated TCR stimulation of activated T cells (ac- clonal expansion of CD8ϩ T cells (by ϳ4–5 log, ϳ1 wk), gener- tivation induced cell death), increasing Fas ligand expression, ating a population of effector cells where up to 50% respond to that which induces apoptosis of neighboring Fasϩ T cells; its role on single infectious agent (1). After infection clearance, there is a mature T and B cell homeostasis is shown by Fas and Fas ligand clonal contraction (by ϳ1–2 log, 8–30 days), leaving a smaller mutants, which trigger progressive lymphadenopathies (12, 13). population of virus-specific memory cells (ϳ5% of the virus-spe- Finally, during the clonal contraction phase of acute primary in- cific CD8ϩ T cells present at the response’s peak), which are main- fections, inflammation wanes, causing a reduction in cytokine ex- tained for years (1, 2). pression and triggering growth factor withdrawal-induced apopto- Recent data have shown that after stimulation, Ag-specific T sis. This apoptotic pathway is independent of Fas-mediated cells continue to divide in a “programmed” Ag-independent man- signaling (14) and strictly dependent on de novo transcription and ner (3–6). Interestingly, the population of epitope-specific CD8ϩ translation (15). It has been suggested that Bcl-2 protein family T cells changes exponentially during both the clonal expansion and members are implicated in this type of apoptosis, requiring the contraction phases (1, 7), where apoptosis plays a prominent role proapoptotic BH3-only member Bim (16). maintaining the system homeostasis. To gain insight on the mechanisms involved in the switch be- Apoptotic cell death plays a critical role not only during T cell tween clonal expansion and clonal contraction phases of CD8ϩ T development, but also for the homeostatic control of peripheral cell responses, the analysis of apoptosis induced by growth factor lymphoid organs and infected tissues, limiting the extent and du- deprivation was undertaken, uncovering the up-regulation of the ration of immune responses and providing a safeguard against im- chemokine receptor CCR2 upon growth factor deprivation. Its spe- munopathology (8–10). Three physiological mechanisms are cific ligand CCL2 significantly inhibited the apoptosis induced by known to trigger apoptosis of Ag-stimulated T cells. The first one IL-2 withdrawal in IL-2-dependent CTL cells, CTLL2 as well as in Ag-activated primary T cells. This inhibition led to an increase in the frequency of cells able to proliferate in response to either ex- Centro de Investigaciones Biolo´gicas, Consejo Superior de Investigaciones Cientı´fi- cas, Madrid, Spain ogenous IL-2 or to a secondary antigenic stimulation. These data ϩ Received for publication September 26, 2007. Accepted for publication September allow hypothesizing that in cytokine-deprived activated CD8 T 26, 2007. cells, CCL2 signaling can modulate the “choice” between survival The costs of publication of this article were defrayed in part by the payment of page and apoptosis; enabling them to migrate toward sites where Ag or charges. This article must therefore be hereby marked advertisement in accordance growth factors are available. with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported by Grants SAF2003-00519 and SAF2006-04903 (to J.A.G.-S.) and SAF2006–4826 (to A.S.) from Spanish Ministry of Education and Materials and Methods Science contracts. Cell lines, culture conditions, and reagents 2 E.D.-G., R.V., and M.J. del P. contributed equally to this work and should be considered as joint first authors. CTLL2 (no. TIB214; American Type Culture Collection) (17) and B6.1 3 Address correspondence and reprint requests to Dr. Jose A. Garcia-Sanz, Centro de (18) are mouse CTL cell clones strictly dependent on exogenous IL-2 for Investigaciones Biolo´gicas, Consejo Superior de Investigaciones Cientı´ficas, Ramiro growth. In CTLL2 cells IL-2 deprivation induces apoptosis, where as this de Maeztu 9, 28040 Madrid, Spain. E-mail address: [email protected] treatment leads to a reversible proliferation arrest in B6.1 cells (19, 20). Cells were cultured in IMDM containing 10% heat-inactivated FCS, 10 Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 mM HEPES (pH 7.0), 0.05 mM 2-ME, 2 mM glutamine and saturating www.jimmunol.org The Journal of Immunology 7353 concentrations of mouse recombinant IL-2 (1% ϫ63 mIL-2 supernatant). cells were resuspended in PBS and stained with PI. For FACS Murine recombinant chemokines (PeproTech) were reconstituted at 0.1 analysis, the whole cell population was analyzed, after exclusion of cell mg/ml in water and used at 200 ng/ml CCL2, 100 ng/ml CCL5, and 10 doublets. ng/ml CXCL9, unless otherwise indicated. Goat anti-mouse CCR2 (CKR2b; Santa Cruz Biotechnology) revealed with a secondary rabbit anti- Limiting dilution analysis goat-FITC (Biomedia), and a PE-conjugated anti-mouse CCR5 Ab (BD Ag-activated primary CD8ϩ Pharmingen), were used at 0.2 ␮g of Ab/106 cells for FACS analysis, as T cells (7–15 days upon activation) were described (21). CCR2 and CCR5 analyses were conducted by gating the deprived of IL-2. Viable cells were FACS sorted and directly collected in 100 ␮ life cell population, which was negative for propidium iodide (PI)4 and l of IMDM, either in the absence or presence of recombinant Ϫ Ϫ IL-2 (100 U/well) or CCL2 (200 ng/ml), onto 96-well plates at 1, 3, 10, Annexin V (PI Annexin V ). or 30 cells/well (24 wells/group). Eighteen hours later, 100 ␮lofme- Primary CD8ϩ T cells and APCs dium containing 400 U/ml recombinant IL-2, either alone or in combi- nation with 100 irradiated APCs, and 2.4 nmol of antigenic peptide ϩ/ϩ Ϫ/Ϫ F5-TCR mice on a Rag1 background (22) were maintained in ho- (NH2-ASNENMDAM-COOH), were added to each well. After a 2-wk mozygosis on a C57BL/6 background. Animals were housed and bred in incubation at 37°C in a 5% CO2 incubator, plates were scored for the our animal facility, and in all experiments were treated in accordance to the presence of live proliferating cells. The frequency of cells able to pro- European Union and National Guide Lines and the Helsinki Declaration. liferate in each experimental condition determined as mean Ϯ SD were ␣ ␤ b The F5-TCR (V 4V 11) is positively selected on the H-2 haplotype; the estimated by interpolating the frequency that contains an average of one ϩ ␣ ϩ ␤ ϩ ϭ mature T cells are MHC class I-restricted CD8 V 4 V 11 , able to rec- precursor cell (F 0.37) on a semi-logarithmic plot containing the ognize the influenza virus A nucleoprotein peptide (366–374) in the con- estimated cells/well and the frequency of negative cultures on a log text of H2-Db (23). As a source of APCs, lymph node or spleen cells from scale. This analysis has been done online using the Bioinformatics fa- Rag2Ϫ/Ϫ animals were purified, x-ray-irradiated (1.4 Gy) and erythrocytes cility of The Walter & Eliza Hall Institute of Medical Research (Mel- removed by ammonium chloride lysis. bourne, Australia) (accessed at http://bioinf.wehi.edu.au/software/ limdil/index.html). Primary CD8ϩ T cell activation Single cell suspensions from lymph nodes of F5-TCRϩ/ϩ mice (1000 cells/ well) were activated with 240 pM antigenic peptide NH2-ASNENMDAM COOH (Isogen Bioscience) in the presence of mouse recombinant IL-2 and irradiated APCs (100 cells/well). Under these conditions, cell numbers reached 7 ϫ 105–1.5 ϫ 106 cells/ml by day 6. IL-2 deprivation For IL-2 deprivation, cells that did not receive fresh IL-2 for the last 48 h were used. Cells were washed twice in fresh medium (300 ϫ g, 10 min), incubated for 30 min at 37°C, and washed once again (300 ϫ g, 10 min) to completely remove IL-2 from the medium and bound to IL-2R.
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