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T Cell Binding to Activated Dendritic Cells Cutting Edge Cutting Edge: CCR4 Mediates Antigen-Primed T Cell Binding to Activated Dendritic Cells Meng-tse Wu, Hui Fang and Sam T. Hwang This information is current as J Immunol 2001; 167:4791-4795; ; of September 27, 2021. doi: 10.4049/jimmunol.167.9.4791 http://www.jimmunol.org/content/167/9/4791 Supplementary http://www.jimmunol.org/content/suppl/2001/10/11/167.9.4791.DC1 Downloaded from Material References This article cites 32 articles, 13 of which you can access for free at: http://www.jimmunol.org/content/167/9/4791.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 27, 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 © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. ● Cutting Edge: CCR4 Mediates Antigen-Primed T Cell Binding to Activated Dendritic Cells Meng-tse Wu, Hui Fang, and Sam T. Hwang1 DC. In the periphery, activated, Ag-bearing DC may bind to cog- The binding of a T cell to an Ag-laden dendritic cell (DC) is a nate effector memory T cells (mTC). In organ culture, mTC-DC critical step of the acquired immune response. Herein, we ad- conjugates have been observed to emigrate from skin of healthy dress whether a DC-produced chemokine can induce the arrest donors (12) and can be found in afferent lymph as well (13). of T cells on DC under dynamic flow conditions. Ag-primed T Chemokines represent a growing family of chemoattractant pro- Downloaded from cells and a T cell line were observed to rapidly (ϳ0.5 s) bind to teins that bind to G protein-coupled (pertussis toxin-sensitive) immobilized DC at low shear stress (0.1–0.2 dynes/cm2)ina transmembrane receptors (14). It has been shown that activated DC pertussis toxin-sensitive fashion. Quantitatively, Ag-primed T may secrete a variety of chemokines (15), including the CCR4 cells displayed 2- to 3-fold enhanced binding to DC compared ligands: CCL22/macrophage-derived chemokine (MDC) (16, 17), with unprimed T cells (p < 0.01). In contrast to naive T cells, and CCL17/thymus and activation-regulated chemokine (TARC) primed T cell arrest was largely inhibited by pertussis toxin, (18, 19). Furthermore, both CCL22 and CCL17 have been shown neutralization of the CC chemokine, macrophage-derived che- to attract Ag-activated (but not naive) T cells in chemotaxis assays http://www.jimmunol.org/ mokine (CCL22), or by desensitization of the CCL22 receptor, in vitro (18, 20). Although integrins appear to be important for T CCR4. Our results demonstrate that DC-derived CCL22 in- cell-DC binding, integrins normally are found in an inactive bind- duces rapid binding of activated T cells under dynamic con- ing state, but can be triggered by chemokines to increase both ditions and that Ag-primed and naive T cells fundamentally affinity and avidity for ligands such as ICAM-1 (21). Therefore, we differ with respect to chemokine-dependent binding to hypothesized that DC-produced chemokines may play critical DC. The Journal of Immunology, 2001, 167: 4791–4795. roles in DC-T cell binding. To test this hypothesis, we immobilized DC to the floor of a parallel plate flow chamber, introduced T cells under low shear by guest on September 27, 2021 cell activation by APCs such as macrophages, B cells, stress, and observed the rapid binding of T cells to DC under and dendritic cells (DC)2 is critical to the development of conditions that could distinguish durable, shear-resistant adhesion T the acquired immune response (1). Such activation occurs from transient juxtaposition. In contrast to the binding of naive T (2) through the development of an intricate assembly of adhesion cells to DC, the binding of Ag-primed T cells to DC was sensitive and signaling molecules at the interface of the APC and T cell to pertussis toxin (PTX) and mediated by CCR4. Thus, chemo- termed the “immunological synapse” (3) or supramolecular acti- kine-mediated binding demonstrated by primed T cells may rep- vation cluster (4). In order for the immunological synapse to form, resent a selective mechanism for allowing Ag-bearing APC to the T cell must transition from a migratory to a stationary state. preferentially engage activated (or memory) vs naive T cells. Adhesive interactions between the T cell and DC, in part stimu- lated by engagement of the TCR (5, 6), have been reported to be Materials and Methods mediated by several adhesion molecules and their corresponding Reagents, animals, cell lines receptors, which include LFA-1/ICAM-1,-2, -3, CD2/LFA-3, and Recombinant murine chemokines/cytokines were purchased from Pepro- DC-SIGN/ICAM-3 (7–10). Tech (Rocky Hill, NJ) unless otherwise specified. Anti-murine CCL22, T cells may potentially interact with DC at several distinct sites. CXCL13, and CCL11 Abs (all neutralizing, affinity-purified goat IgG) Naive as well as a central memory subset of T cells (11), both were purchased from R&D Systems (Minneapolis, MN). BALB/c and DO11.10 (OVA peptide 323–339-specific) TCR-trans- characterized by expression of CD62L (L-selectin) and CCR7, re- genic mice on a BALB/c background (22) (The Jackson Laboratory, Bar circulate through lymph nodes (LN) and interact with Ag-bearing Harbor, ME) were used in institutionally approved protocols. The T cell hybridoma cell line, B 9.1, is specific for the MHC II-restricted, immuno- dominant hen egg-white lysozyme (HEL) peptide 103–117 (23). BALB/c bone marrow-derived DC (BMDC) were generated as described (24) and Dermatology Branch, National Cancer Institute, Bethesda, MD 20892 cultured in complete medium with RPMI 1640, 5% FCS, IL-4 (10 ng/ml), Received for publication July 30, 2001. Accepted for publication September 4, 2001. GM-CSF (10 ng/ml), and Flt3 ligand (R&D Systems). BMDC were used The costs of publication of this article were defrayed in part by the payment of page on day 9–12 when Ͼ83% of nonadherent cells expressed CD11c, CD40, charges. This article must therefore be hereby marked advertisement in accordance CD80, CD86, and I-Ad by flow cytometry. BMDC showed a 6-fold re- with 18 U.S.C. Section 1734 solely to indicate this fact. sponse to CCL21 vs PBS in chemotaxis assays and no response to CCL5. 1 Address correspondence and reprint requests to Dr. Sam T. Hwang, Dermatology Real-time quantitative RT-PCR was performed as described (25). Branch, National Cancer Institute, Building 10, Room 12N246, 10 Center Drive, In vivo-enriched OVA-primed T cells were generated by s.c. immuniz- Bethesda, MD 20892-1908. E-mail address: [email protected] ing DO11.10-transgenic mice with OVA peptide 323–339 (200 ␮g per 2 mouse) in CFA. Five to 7 days after the immunization, cells from enlarged Abbreviations used in this paper: DC, dendritic cell; LN, lymph node; BMDC, bone ϩ ϩ marrow-derived DC; mTC, memory T cell; nTC, naive T cell; MDC, macrophage- draining LN were pooled and depleted of CD19 and CD40 cells by derived chemokine; TARC, thymus and activation-regulated chemokine; PTX, per- immunomagnetic bead depletion. Naive OVA-specific T cells were iso- tussis toxin; HEL, hen egg-white lysozyme. lated from LN and spleen of DO11.10 mice by identical depletion methods. Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 ● 4792 CUTTING EDGE: CCR4-MEDIATED T CELL BINDING TO DC After selection, the resulting cells were ϳ97% CD3eϩ cells and ϳ82% CD4ϩ cells by flow cytometric analysis. In vitro flow arrest assay For immobilization of BMDC, a droplet of anti-mouse CD40 (HM40-3, 10 ␮g/ml in 100 ␮l PBS; BD PharMingen, San Diego, CA) was first centrally applied to 35-mm plastic dishes at 4°C overnight and then blocked with PBS/1% BSA for 45 min at 25°C. Day 9–12 BMDC (1 ϫ 106/ml, 100 ␮l for each dish) were then applied to the anti-CD40-coated plates for 2.5 h at 4°C. For quantitative analysis of T cell arrest, B 9.1 cells and T cells were labeled with calcein-AM (Molecular Probes, Eugene, OR) and ex- posed to different reagents as indicated: chemokines (25 ng/ml for 30 min at 37°C), anti-chemokines Abs (ant-CCL11, anti-CCL22, and anti- CXCL13 at 2.5 ␮g/ml for 5 min before flow experiments at 20°C), and PTX (100 ng/ml for2hat37°C; Calbiochem, La Jolla, CA). T cells (1 ϫ 106/ml) were resuspended into a 12-ml syringe and introduced into a par- allel plate flow chamber (Glycotech, Rockville, MD) that was affixed to the dish containing immobilized DC. Flow was adjusted to shear stresses of 0.2 (for B 9.1 cells) and 0.1 dynes/cm2 (for DO11.10-derived T cells). Four min after cells entered the chamber, a series of eight images from randomly 2 selected fields (1.18 mm /field) in different quadrants of the dish were Downloaded from video-captured using a ϫ4 objective under fluorescent illumination.
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