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Chemokines Upon Activation CXCL12 And The Journal of Immunology ● Cutting Edge: IFN-Producing Cells Respond to CXCR3 Ligands in the Presence of CXCL12 and Secrete Inflammatory Chemokines upon Activation1 Anne Krug,* Ravindra Uppaluri,† Fabio Facchetti,‡ Brigitte G. Dorner,* Kathleen C. F. Sheehan,* Robert D. Schreiber,* Marina Cella,* and Marco Colonna2* from the blood to inflamed lymph nodes through HEV. Consistent Human natural IFN-producing cells (IPC) circulate in the with this hypothesis, human blood IPC express L-selectin and blood and cluster in chronically inflamed lymph nodes around CXCR3, the receptor for the inflammatory chemokines CXCL9 high endothelial venules (HEV). Although L-selectin, CXCR4, (monokine induced by IFN-␥), CXCL10 (IFN-␥-inducible protein and CCR7 are recognized as critical IPC homing mediators, 10), and CXCL11 (IFN-␥-inducible T cell ␣ chemoattractant) (4). the role of CXCR3 is unclear, since IPC do not respond to However, it has been shown that human IPC do not migrate in CXCR3 ligands in vitro. In this study, we show that migration vitro in response to CXCR3 ligands (5). Similarly, IPC do not of murine and human IPC to CXCR3 ligands in vitro requires respond in vitro to CCL3 (macrophage-inflammatory protein 1 engagement of CXCR4 by CXCL12. We also demonstrate that (MIP-1␣)), CCL4 (MIP-1␤), and CCL5 (RANTES) despite the CXCL12 is present in human HEV in vivo. Moreover, after expression of CCR5 (5). Human IPC also express CXCR4 and interaction with pathogenic stimuli, murine and human IPC respond to the CXCR4 ligand CXCL12 in vitro (5, 6). Importantly, secrete high levels of inflammatory chemokines. Thus, IPC CXCL12 secreted by some tumors attracts IPC and protects them migration into inflamed lymph nodes may be initially me- from IL-10-induced apoptosis in vivo (6). Upon activation with diated by L-selectin, CXCL12, and CXCR3 ligands. Upon pathogenic stimuli, IPC up-regulate CCR7 and migrate in re- pathogen encounter, IPC positioning within the lymph node sponse to the CCR7 ligands CCL19 (EBV-induced molecule 1 may be further directed by CCR7 and IPC secretion of in- ligand chemokine/MIP-3␤) and CCL21 (secondary lymphoid flammatory chemokines may attract other IPC, promoting tissue chemokine) (5, 7, 8). cluster formation in lymph nodes. The Journal of Immu- Murine IPC have been recently identified (9–12) and found to nology, 2002, 169: 6079–6083. be significantly reduced in number in the spleen of L-selectin- deficient mice (9), corroborating a role of L-selectin in IPC mi- atural IFN-producing cells (IPC)3 are a small population gration through HEV. Murine IPC can be cultured in vitro in rel- of leukocytes with a plasma cell-like morphology that atively large numbers (13), providing the opportunity to further N are specialized in the secretion of type I IFN (i.e., IFN-␣, investigate the mechanisms of IPC homing. In this study, we show IFN-␤, and IFN-␻) in response to certain viruses (1–4). Human that murine IPC cultured from bone marrow (BM) express L-se- IPC have been found in the blood and in lymph nodes affected by lectin, CXCR4, and CXCR3 and migrate poorly in vitro in re- inflammation, clustered around high endothelial venules (HEV) sponse to CXCR3 ligands, like human IPC. Remarkably, we find (4). This anatomical localization has suggested that IPC migrate that CXCL12 restores responsiveness of murine and human IPC to CXCR3 ligands in vitro and that CXCL12 is present in HEV in Departments of *Pathology and Immunology and †Otolaryngology, Washington Uni- vivo. Following stimulation with viruses, CpG oligonucleotides, or versity School of Medicine, St. Louis, MO 63110; and ‡Istituto di Anatomia Pato- cells expressing CD40 ligand (L), IPC secrete inflammatory che- logica, Universita´ di Brescia, Spedali Civili di Brescia, Brescia, Italy mokines, which may attract other IPC, promoting cluster forma- Received for publication July 8, 2002. Accepted for publication October 2, 2002. tion in secondary lymphoid organs. 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. 1 A.K. was supported by the Deutsche Forschungsgemeinschaft (KR 2199/1-1). Materials and Methods R.I.U. and R.D.S. were supported by the National Cancer Institute (CA90403, CA76464). Preparation, culture, and stimulation of cells 2 Address correspondence and reprint requests to Dr. Marco Colonna, Department of Murine BM cells from 129 ϫ 1/SvJ mice (The Jackson Laboratory, Bar Pathology and Immunology, Washington University School of Medicine, 660 South Harbor, ME) were cultured in Flt3-L (10 ng/ml; R&D Systems, Minneap- Euclid, Box 8118, St. Louis, MO 63110. E-mail address: mcolonna@pathology. ϫ 6 wustl.edu olis, MN) at 2–4 10 cells/ml for 7–9 days and were sorted into CD11cϩ/CD11blow and CD11cϩ/CD11bhigh subpopulations on a MoFlo 3 Abbreviations used in this paper: IPC, natural IFN-producing cell; HEV, high en- cytometer (purity Ͼ95%; Cytomation, Fort Collins, CO). Human IPC were dothelial venule; IP-10, IFN-␥-inducible protein 10; I-TAC, IFN-␥-inducible T cell ␣ chemoattractant; MIP, macrophage-inflammatory protein; L, ligand; BM, bone mar- isolated and cultured as described previously (4, 7). Cells were stimulated row; Mo-DC, monocyte-derived dendritic cell; DC, dendritic cell; m, mouse; h, with CpG oligonucleotide 2216 (3 ␮g/ml) (14), influenza virus PR8 (0.1–1 human. multiplicity of infection), and CD40L-transfected J558L cells (4). Copyright © 2002 by The American Association of Immunologists, Inc. 0022-1767/02/$02.00 ● 6080 CUTTING EDGE: CXCL12 INDUCES IPC RESPONSIVENESS TO CXCR3 LIGANDS Abs, flow cytometry, and ELISA Anti-mouse (m) CXCR3 mAb 173 was generated by immunizing male Armenian hamsters with a peptide containing the amino-terminal 37 resi- dues of mCXCR3. This peptide sequence is unique to mCXCR3. Anti- mCXCL9 mAb 2F.5.5.5 was generated by immunizing male Armenian hamsters with recombinant mCXCL9 (R&D Systems). Specificity of 2F.5.5.5 was confirmed by ELISA (data not shown). Anti-mCXCL10 1F11 was kindly provided by A. D. Luster (15). Anti-mCXCR3 was either con- jugated with FITC or detected by biotinylated goat anti-hamster Ab (Jack- son ImmunoResearch Laboratories, West Grove, PA) and streptavidin-al- lophycocyanin (Molecular Probes, Eugene, OR). Cells were counterstained with directly labeled rat anti-mouse CD11c, CD62L, CD11b, or CD86 (BD PharMingen, San Diego, CA). Goat anti-mCXCR4 antiserum (Santa Cruz Biotechnology, Santa Cruz, CA) was detected with biotinylated donkey anti-goat antiserum (Jackson ImmunoResearch) and streptavidin-allophy- cocyanin (Molecular Probes). Murine intracellular CCL3, CCL4, and CCL5 were detected as described elsewhere (16). Human intracellular che- mokines were detected with directly labeled Abs (BD PharMingen and R&D Systems). mCXCL9 and mCXCL10 were measured in the superna- tant by ELISA using monoclonal hamster anti-mCXCL9 (5 ␮g/ml) and anti-mCXCL10 (2.5 ␮g/ml), goat anti-mCXCL9 (1 ␮g/ml; R&D Systems), or anti-mCXCL10 (0.2 ␮g/ml; Santa Cruz Biotechnology), biotinylated anti-goat Ab (Vector Laboratories, Burlingame, CA), and avidin-HRP (Sigma-Aldrich, St. Louis, MO). Human CXCL10 and CCL3 were de- tected by ELISA using matched Ab pairs (BD PharMingen and R&D Sys- tems). ABTS (Sigma-Aldrich) was used as substrate. Chemotaxis assay Chemotaxis was measured in a 2-h transwell migration assay using 24-well Costar Transwell chambers (5-␮m pore size; Corning, Cambridge, MA) as described previously (5). Recombinant mCXCL12, mCXCL10, mCXCL11, and human (h) CXCL11 (PeproTech, Rocky Hill, NJ) were added to the lower wells in chemotaxis medium (RPMI 1640/1% human serum albumin), and 1 ϫ 105 cells were added to the Transwell insert. Migrated cells were counted by microscopy and flow cytometry. Where indicated, cells were pretreated with pertussis toxin (100 ng/ml; Sigma- Aldrich) for1hat37°C. FIGURE 1. Expression of L-selectin, CXCR3, and CXCR4 on murine BM-derived IPC. A, Expression of CXCR3 and CD62L on CD11blow IPC. Expression of CXCR3 and L-selectin on CD11bhigh DC was minimal. Gate Immunohistochemistry is set on CD11cϩ cells from Flt3-L-cultured murine BM cells. B, Expres- sion of CXCR3 and CXCR4 on CD11cϩ/CD11blow IPC. C, Expression of Immunohistochemical analysis of Formalin-fixed, paraffin-embedded ϩ ϩ lymph node sections was done as described elsewhere (17) using mono- CXCR3 on Ly-6G/C cells within CD11c DC purified from spleen. D, ϩ clonal anti-hCXCL12 Ab K15C (kindly provided by F. Arenzana-Seis- Down-regulation of CXCR3 and CD62L on gated CD11c cells from Flt3- dedos (18)). L-cultured murine BM cells after incubation for 24 h with influenza virus. E, Kinetics of CXCR3 (f, F) and CD86 (Ⅺ, E) expression in unstimu- lated (F, E)orinfluenza virus-stimulated (f, Ⅺ) Flt3-L-cultured BM cells Results (gated on CD11cϩ/CD11blow IPC). F, Migratory response to CCL19 (f)or Murine IPC express L-selectin, CXCR3, and CXCR4 control medium (Ⅺ) of CD11blow IPC stimulated with influenza virus. G, Dose-dependent down-regulation of CXCR3 on Flt3L-cultured BM cells Murine BM cells cultured in vitro with Flt3-L were highly en- by treatment with CXCL11 and CXCL10 (30 min, 37°C). riched in CD11cϩcells that included CD11blow and CD11bhigh populations. CD11blow cells expressed high levels of B220, Ly6- G/C and secreted type I IFN upon incubation with influenza virus and CpG oligonucleotides (Ref. 13 and data not shown). There- fore, CD11blow cells correspond to IPC in phenotype and function. CXCL12 induces responsiveness of IPC to CXCR3 ligands in As shown in Fig. 1A, CD11blow IPC expressed CXCR3 and L- vitro and is present in HEV in vivo selectin (CD62L). In addition, CXCR3ϩ IPC expressed CXCR4 It has been previously shown that human IPC migrate poorly in (Fig.
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