ABSTRACT
The Human Chemokine (C-C motif) ligand 19 (CCL19) protein plays a major role in rheumatic and autoimmune diseases. The 3D models of the CCL19 and its receptor CCR7 are generated using homology modeling and are validated using standard computational protocols. Disulfide bridges identified in 3D model of CCL19 protein give extra stability to the overall protein structure. The active site region of protein CCL19, containing N-terminal amino acid residues (Gly22 to Leu31), is predicted using in silico techniques. Protein-protein docking studies are carried out between the CCL19 and CCR7 proteins to analyse the active site binding interactions of CCL19. The binding domain of CCL19 is subjected to structure-based virtual screening of small molecule databases, and identified several bioisosteric ligand molecules having pyrrolidone and piperidone pharmacophores. The prioritized ligands with acceptable ADME properties are reported as new leads for the design of potential CCL19 antagonists for rheumatic and autoimmune disease therapies.
Subject(s)
Autoimmune Diseases/drug therapy , Chemokine CCL19/chemistry , Chemokine CCL19/metabolism , Computer Simulation , Receptors, CCR7/chemistry , Receptors, CCR7/metabolism , Rheumatic Diseases/drug therapy , Amino Acid Sequence , Catalytic Domain , Conserved Sequence , Disulfides/metabolism , Drug Evaluation, Preclinical , Humans , Ligands , Molecular Docking Simulation , Protein Binding , Protein Domains , Protein Structure, Secondary , Solvents , Structural Homology, ProteinABSTRACT
The mammalian gastrointestinal tract harbors a microbial community with metabolic activity critical for host health, including metabolites that can modulate effector functions of immune cells. Mice treated with vancomycin have an altered microbiome and metabolite profile, exhibit exacerbated T helper type 2 cell (Th2) responses, and are more susceptible to allergic lung inflammation. Here we show that dietary supplementation with short-chain fatty acids (SCFAs) ameliorates this enhanced asthma susceptibility by modulating the activity of T cells and dendritic cells (DCs). Dysbiotic mice treated with SCFAs have fewer interleukin-4 (IL4)-producing CD4+ T cells and decreased levels of circulating immunoglobulin E (IgE). In addition, DCs exposed to SCFAs activate T cells less robustly, are less motile in response to CCL19 in vitro, and exhibit a dampened ability to transport inhaled allergens to lung draining nodes. Our data thus demonstrate that gut dysbiosis can exacerbate allergic lung inflammation through both T cell- and DC-dependent mechanisms that are inhibited by SCFAs.
Subject(s)
Asthma/immunology , Dendritic Cells/immunology , Dysbiosis/immunology , Fatty Acids, Volatile/administration & dosage , Hypersensitivity/immunology , Pneumonia/immunology , Th2 Cells/immunology , Allergens/immunology , Animals , Antigen Presentation , Asthma/prevention & control , Chemokine CCL19/metabolism , Dietary Supplements , Dysbiosis/prevention & control , Gastrointestinal Microbiome/immunology , Hypersensitivity/prevention & control , Interleukin-4/genetics , Interleukin-4/metabolism , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Knockout , Microbiota/immunology , Pneumonia/prevention & control , Vancomycin/administration & dosageABSTRACT
Baicalin, extracted and purified from the Chinese medicinal plant, Scutellaria baicalensis Georgi (Huang qin in Chinese), exhibits potent anti-inflammatory activity against asthma. However, it remains unknown whether baicalin inhibits the activity of CC chemokine receptor 7 (CCR7) and its ligands, which are crucial for the initiation of airway inflammation. In the present study, we investigated the effects of baicalin on CCR7 and its ligands, CCL19 and CCL21, as well as on the nuclear factor-κB (NF-κB) pathway in a mouse model of asthma. A mouse model of acute asthma was established by exposing the mice to ovalbumin (OVA) (by intraperitoneal injection and inhalational challenge). Within 24 h of the final OVA challenge, lung function was detected by direct airway resistance analysis. Lung tissues were examined for pathological changes. Inflammatory cell counts in bronchoalveolar lavage fluid (BALF) were assessed. ELISA was utilized to evaluate the OVA-IgE, CCL19 and CCL21 levels in BALF. The interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels in serum were also detected by ELISA. The protein expression levels of CCR7, as well as that of phosphorylated IκBα (p-IκBα) and phosphorylated p65 (p-p65) were determined by western blot analysis and RT-qPCR was used to determine the CCR7 mRNA levels. Our data demonstrated that the oral administration of baicalin significantly improved pulmonary function and attenuated inflammatory cell infiltration into the lungs. Baicalin also decreased the levels of OVA-IgE, IL-6, TNF-α and CCR7, as well as those of its ligand, CCL19; the levels of NF-κB were also markedly suppressed by baicalin. The CCR7 mRNA level was substantially decreased. Our results thus suggest that baicalin exerts an inhibitory effect on airway inflammation, and this effect may be associated with the inhibition of CCR7 and CCL19/CCL21, which may provide new mechanistic insight into the antiinflammatory effects of baicalin.
Subject(s)
Asthma/prevention & control , Chemokine CCL19/metabolism , Chemokine CCL21/metabolism , Flavonoids/pharmacology , Inflammation/prevention & control , NF-kappa B/metabolism , Receptors, CCR7/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Asthma/chemically induced , Asthma/metabolism , Blotting, Western , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , Disease Models, Animal , Female , Flavonoids/chemistry , Humans , Inflammation/genetics , Inflammation/metabolism , Interleukin-6/blood , Interleukin-6/metabolism , Lung/drug effects , Lung/metabolism , Lung/pathology , Mice, Inbred BALB C , Molecular Structure , Ovalbumin , Receptors, CCR7/genetics , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/blood , Tumor Necrosis Factor-alpha/metabolismABSTRACT
There remain significant obstacles in developing biologics to treat primary biliary cholangitis (PBC). Although a number of agents have been studied both in murine models and human patients, the results have been relatively disappointing. IL-22 is a member of the IL-10 family and has multiple theoretical reasons for predicting successful usage in PBC. We have taken advantage of an IL-22 expressing adeno-associated virus (AAV-IL-22) to address the potential role of IL-22 in not only protecting mice from autoimmune cholangitis, but also in treating animals with established portal inflammation. Using our established mouse model of 2-OA-OVA immunization, including α-galactosylceramide (α-GalCer) stimulation, we treated mice both before and after the onset of clinical disease with AAV-IL-22. Firstly, AAV-IL-22 treatment given prior to 2-OA-OVA and α-GalCer exposure, i.e. before the onset of disease, significantly reduces the portal inflammatory response, production of Th1 cytokines and appearance of liver fibrosis. It also reduced the liver lymphotropic chemokines CCL5, CCL19, CXCL9, and CXCL10. Secondly, and more importantly, therapeutic use of AAV-IL-22, administered after the onset of disease, achieved a greater hurdle and significantly improved portal pathology. Further the improvements in inflammation were negatively correlated with levels of CCL5 and CXCL10 and positively correlated with levels of IL-22. In conclusion, we submit that the clinical use of IL-22 has a potential role in modulating the inflammatory portal process in patients with PBC.
Subject(s)
Autoimmune Diseases/therapy , Biological Therapy/methods , Cholangitis/therapy , Interleukins/immunology , Liver/immunology , Portal System/immunology , Animals , Chemokine CCL19/immunology , Chemokine CCL19/metabolism , Chemokine CCL5/immunology , Chemokine CCL5/metabolism , Chemokine CXCL10/immunology , Chemokine CXCL10/metabolism , Chemokine CXCL9/immunology , Chemokine CXCL9/metabolism , Dependovirus , Disease Models, Animal , Female , Galactosylceramides/immunology , Galactosylceramides/pharmacology , Genetic Vectors , Interleukins/genetics , Liver/blood supply , Liver Cirrhosis, Biliary/immunology , Liver Cirrhosis, Biliary/therapy , Mice , Mice, Inbred C57BL , Portal System/pathology , Interleukin-22ABSTRACT
The chemotactic movement of T lymphocytes mediated by chemokines and their receptors plays an important role in the pathogenesis of graft-versus-host disease (GVHD) post-allogeneic hematopoietic stem cell transplantation (allo-HSCT). CCR7 and CXCR3 are two receptors associated with the development of GVHD. Bortezomib, a proteasome inhibitor, was recently found to prevent GVHD in a mouse model and to decrease the production of Th1 cytokines. Here, we report that bortezomib differentially regulates the expression of CXCR3 and CCR7 on T cells; it significantly decreases CXCR3 expression on T cells as well as its CD4(+)/CD8(+) subsets in a dose-dependent manner, while it does not significantly affect CCR7 expression on T cells and subsets. Moreover, the secretion of CXCL9 by activated T cells is also increasingly downregulated with increasing concentrations of bortezomib. Meanwhile, bortezomib inhibits T-cell chemotactic movements toward CXCL9 in a dose-dependent manner, but has no effect on CCL19-induced T-cell chemotaxis. Additionally, it was found that bortezomib treatment also prompts T-lymphocyte apoptosis through activation of caspase-3 and its downstream PARP cleavage in a dose- and time-dependent manner. These results suggest that bortezomib may act as a suppressor of GVHD by downregulating T-cell chemotatic movement toward GVHD target organs, as well as by inducing apoptosis.
Subject(s)
Apoptosis/drug effects , Boronic Acids/pharmacology , Chemokine CXCL9/metabolism , Chemotaxis/drug effects , Protease Inhibitors/pharmacology , Pyrazines/pharmacology , Receptors, CXCR3/biosynthesis , T-Lymphocyte Subsets/drug effects , Adult , Bortezomib , Cells, Cultured , Chemokine CCL19/physiology , Depression, Chemical , Down-Regulation , Drug Evaluation, Preclinical , Graft vs Host Disease/drug therapy , Humans , Lymphocyte Activation/drug effects , Mitogen-Activated Protein Kinase 1/metabolism , Phosphorylation , Protein Processing, Post-Translational , Receptors, CCR7/biosynthesis , Receptors, CCR7/genetics , Receptors, CXCR3/genetics , T-Lymphocyte Subsets/metabolismABSTRACT
Metastatic squamous cell carcinoma of the head and neck (SCCHN) has been shown to express chemokine receptor 7 (CCR7), which activates phosphoinositide-3 kinase (PI3K) to promote invasion and survival of SCCHN cells. We hypothesized that Cdc42 might be involved in the CCR7-PI3K pathway. Adhesion assays, migration assays, immunofluorescence staining, Western blotting and immunohistochemical analysis were used to find whether Cdc42 can be activated by CCL19 (the CCR7 ligand) and its role in SCCHN. Results showed that CCL19 induced polarized localization of Cdc42 and actin polymerization in the leading edge of migrating cells. The level of activated membrane-bound Cdc42 was elevated, as measured by the GTPase activity pull-down assay. The increased membrane localization and membrane-bound activity of Cdc42 were abolished by CCR7 and PI3K inhibition, indicating the involvement of Cdc42 in the CCR7-PI3K cascade. Knockdown of Cdc42 by small interfering RNA (siRNA) led to significant reduction in the activation of Rac, filamentous actin (F-actin) accumulation as well as in the migration and invasion induced by CCL19. Taken together, our data indicate the important role played by Cdc42 in CCL19-induced migration and invasion of SCCHN cells.
Subject(s)
Chemokine CCL19/pharmacology , Phosphatidylinositol 3-Kinases/physiology , Receptors, CCR7/agonists , Receptors, CCR7/physiology , cdc42 GTP-Binding Protein/physiology , Adult , Aged , Aged, 80 and over , Carcinoma/genetics , Carcinoma/metabolism , Carcinoma/pathology , Carcinoma, Squamous Cell , Cell Movement/drug effects , Cell Movement/genetics , Chemokine CCL19/metabolism , Drug Evaluation, Preclinical , Female , Gene Expression Regulation, Neoplastic/drug effects , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/metabolism , Head and Neck Neoplasms/pathology , Humans , Male , Middle Aged , Neoplasm Invasiveness , Neoplasm Metastasis , Neoplasms, Squamous Cell/genetics , Neoplasms, Squamous Cell/metabolism , Neoplasms, Squamous Cell/pathology , Phosphatidylinositol 3-Kinases/metabolism , RNA, Small Interfering/pharmacology , Receptors, CCR7/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Signal Transduction/physiology , Squamous Cell Carcinoma of Head and Neck , Tumor Cells, Cultured , cdc42 GTP-Binding Protein/antagonists & inhibitors , cdc42 GTP-Binding Protein/genetics , cdc42 GTP-Binding Protein/metabolismABSTRACT
Inhibition of dendritic cell (DC) migration into tissues and secondary lymphoid organs is an efficient way to induce immunosuppression and tolerance. CCR7 and PGE(2) are critical for DC migration to secondary lymphoid organs where DC initiate immune response. Triptolide, an active component purified from the medicinal plant Tripterygium Wilfordii Hook F., is a potent immunosuppressive drug capable of prolonging allograft survival in organ transplantation by inhibiting T cell activation and proliferation. Considering the essential role in T cell tolerance of DC migration to secondary lymphoid organs, here we demonstrate that triptolide can significantly inhibit LPS-triggered upregulation of CCR7 expression and PGE(2) production by inhibiting cyclooxygenase-2 (COX-2) expression in DC, thus impairing DC migration towards CCR7 ligand CCL19/MIP-3betain vitro. Moreover, triptolide-treated DC display impaired migration into secondary lymphoid organs and in vivo administration of triptolide also inhibits DC migration. Further studies show that the triptolide-mediated inhibitory effects of LPS-induced activation of phosphatidylinositol-3 kinase (PI3-K)/Akt and nuclear NF-kappaB activation are involved in down-regulation of COX-2 and CCR7 expression resulting in impaired migration to secondary lymphoid organs of DC. Therefore, inhibition of DC migration through decreasing COX-2 and CCR7 expression via PI3-K/Akt and NF-kappaB signal pathways provides additional mechanistic explanation for triptolide's immunosuppressive effect.
Subject(s)
Cell Movement/drug effects , Cyclooxygenase 2/metabolism , Dendritic Cells/drug effects , Diterpenes/pharmacology , Immunosuppressive Agents/pharmacology , Phenanthrenes/pharmacology , Receptors, Chemokine/antagonists & inhibitors , Animals , Chemokine CCL19 , Chemokines, CC/metabolism , Cytokines/metabolism , Dinoprostone/metabolism , Epoxy Compounds/pharmacology , Lipopolysaccharides/pharmacology , Male , Mice , Mice, Inbred C57BL , NF-kappa B/antagonists & inhibitors , Phosphoinositide-3 Kinase Inhibitors , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Receptors, CCR7 , Receptors, Chemokine/metabolismABSTRACT
Triptolide (TPT) is a chemically defined, potent immunosuppressive compound isolated from an anti-inflammatory Chinese herbal medicine. TPT has been reported to inhibit autoimmunity, allograft rejection, and graft-versus-host disease (GVHD), and its efficacy was previously attributed to the suppression of T cells. Since dendritic cells (DCs) play a major role in the initiation of T-cell-mediated immunity, we studied the effects of TPT on the phenotype, function, and migration of human monocyte-derived DCs. TPT treatment, over a pharmacologic concentration range, inhibited the lipopolysaccharide (LPS)-induced phenotypic changes, characteristic of mature DCs and the production of interleukin-12p70 (IL-12p70). Consequently, the allostimulatory functions of DCs were impaired by TPT treatment. Furthermore, the calcium mobilization and chemotactic responses of LPS-stimulated DCs to secondary lymphoid tissue chemokine (SLC)/CC chemokine ligand 21 (CCL21) were significantly lower in TPT-treated than untreated DCs, in association with lower chemokine receptor 7 (CCR7) and higher CCR5 expression. Egress of Langerhans cells (LCs) from explanted mouse skin in response to macrophage inflammatory protein-3beta (MIP-3beta)/CCL19 was arrested by TPT. In vivo administration of TPT markedly inhibited hapten (fluorescein isothiocyanate [FITC])-stimulated migration of mouse skin LCs to the draining lymph nodes. These data provide new insight into the mechanism of action of TPT and indicate that the inhibition of maturation and trafficking of DCs by TPT contributes to its immunosuppressive effects.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Dendritic Cells/cytology , Diterpenes/chemistry , Diterpenes/pharmacology , Drugs, Chinese Herbal/pharmacology , Immunosuppressive Agents/pharmacology , Phenanthrenes/chemistry , Phenanthrenes/pharmacology , Animals , Apoptosis , Autoimmunity , CD3 Complex/biosynthesis , CD4-Positive T-Lymphocytes/cytology , Calcium/metabolism , Cell Differentiation , Cell Movement , Cell Separation , Chemokine CCL19 , Chemokine CCL21 , Chemokines, CC/metabolism , Cytokines/metabolism , Dose-Response Relationship, Drug , Down-Regulation , Epidermis/metabolism , Epoxy Compounds , Female , Flow Cytometry , Fluorescein-5-isothiocyanate/pharmacology , Interleukin-12/metabolism , Langerhans Cells/cytology , Leukocytes, Mononuclear/cytology , Lipopolysaccharides/metabolism , Lymph Nodes/pathology , Mice , Mice, Inbred BALB C , Monocytes/cytology , Monocytes/metabolism , Phenotype , Protein Subunits/metabolism , Receptors, CCR5/metabolism , Skin/metabolismABSTRACT
Human herpesvirus 7 (HHV-7), which belongs to the betaherpesvirus subfamily, infects mainly CD4+ T cells in vitro and infects children during infancy. After the primary infection, HHV-7 becomes latent. HHV-7 contains two genes (U12 and U51) that encode putative homologs of cellular G-protein-coupled receptors. To analyze the biological function of the U12 gene, we cloned the gene and expressed the U12 protein in cells. The U12 gene encoded a calcium-mobilizing receptor for the EBI1 ligand chemokine-macrophage inflammatory protein 3beta (ELC/MIP-3beta) but not for other chemokines, suggesting that the chemokine selectivity of the U12 gene product is distinct from that of the known mammalian chemokine receptors. These studies revealed that U12 activates distinct transmembrane signaling pathways that may mediate biological functions by binding with a beta-chemokine, ELC/MIP-3beta.
Subject(s)
Chemokines, CC/metabolism , Herpesvirus 7, Human/genetics , Open Reading Frames , Receptors, Chemokine/genetics , Receptors, Chemokine/metabolism , Amino Acid Sequence , Cell Line , Chemokine CCL19 , Chemokines, CC/chemistry , Chemokines, CC/genetics , Cloning, Molecular , DNA, Complementary , Humans , Molecular Sequence Data , Polymerase Chain Reaction , Receptors, Chemokine/chemistry , Sequence Alignment , Signal TransductionABSTRACT
We report here the identification and characterization of murine CCX-CKR, a high affinity receptor for the murine beta-chemokines SLC/mCCL21, MIP-3beta/mCCL19 and TECK/mCCL25. Unlike most other chemokine receptors, CCX-CKR is unable to mediate Ca(2+) fluxes upon ligand binding when expressed in HEK293 cells. Murine CCX-CKR is expressed predominantly in the heart and lung, but is detectable in most organs using RT-PCR. Interestingly, in brain and testis, an alternative mRNA form of CCX-CKR exists with a unique 5' untranslated region (5'UTR) that overlaps with a novel acyl-CoA dehydrogenase (ACD) gene. Analysis of human CCX-CKR shows that the expression profiles and alternative 5'UTR are conserved. However, in man, there are two copies of the CCX-CKR gene, one on chromosome 3 nestled within the ACD homologue, and one on chromosome 6. These genes encode proteins with only one amino acid difference, and their expression is independently regulated. This study identifies murine CCX-CKR, reveals complex regulation of CCX-CKR gene expression in mouse and man, and is suggestive of non-leukocytic targets for MIP-3beta/CCL19, SLC/CCL21 and TECK/CCL25.
Subject(s)
Chemokines, CC/metabolism , Receptors, Chemokine/metabolism , 5' Untranslated Regions , Alternative Splicing , Amino Acid Sequence , Animals , Base Sequence , Brain/immunology , Brain/metabolism , Calcium Signaling , Cell Line , Chemokine CCL19 , Chemokine CCL21 , Cloning, Molecular , DNA, Complementary/genetics , Gene Expression , Humans , Leukocytes/immunology , Leukocytes/metabolism , Ligands , Male , Mice , Molecular Sequence Data , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Chemokine/genetics , Sequence Homology, Amino Acid , Species Specificity , Testis/immunology , Testis/metabolismABSTRACT
We report that the addition of human macrophage inflammatory protein-3 beta (MIP-3 beta) to cultures of human PBMCs that have been activated with LPS or PHA results in a significant enhancement of IL-10 production. This effect was concentration-dependent, with optimal MIP-3 beta concentrations inducing more than a 5-fold induction of IL-10 from LPS-stimulated PBMCs and a 2- to 3-fold induction of IL-10 from PHA-stimulated PBMCs. In contrast, no significant effect on IL-10 production was observed when 6Ckine, the other reported ligand for human CCR7, or other CC chemokines such as monocyte chemoattractant protein-1, RANTES, MIP-1 alpha, and MIP-1 beta were added to LPS- or PHA-stimulated PBMCs. Similar results were observed using activated purified human peripheral blood monocytes or T cells. Addition of MIP-3 beta to nonactivated PBMCs had no effect on cytokine production. Enhancement of IL-10 production by MIP-3beta correlated with the inhibition of IL-12 p40 and TNF-alpha production by monocytes and with the impairment of IFN-gamma production by T cells, which was reversed by addition of anti-IL-10 Abs to the cultures. The ability of MIP-3 beta to augment IL-10 production correlated with CCR7 mRNA expression and stimulation of intracellular calcium mobilization in both monocytes and T cells. These data indicate that MIP-3 beta acts directly on human monocytes and T cells and suggest that this chemokine is unique among ligands binding to CC receptors due to its ability to modulate inflammatory activity via the enhanced production of the anti-inflammatory cytokine IL-10.
Subject(s)
Adjuvants, Immunologic/physiology , Chemokines, CC/physiology , Interleukin-10/biosynthesis , Lymphocyte Activation/immunology , Monocytes/immunology , Monocytes/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Cells, Cultured , Chemokine CCL19 , Chemokine CCL21 , Cytokines/antagonists & inhibitors , Humans , Immunosuppressive Agents/pharmacology , Inflammation/immunology , Inflammation/prevention & control , Interleukin-10/physiology , Lipopolysaccharides/pharmacology , Phytohemagglutinins/pharmacologyABSTRACT
By searching the expressed sequence tag (EST) data base, we identified partial cDNA sequences encoding a novel human CC chemokine. We determined the complete cDNA sequence that encodes a highly basic polypeptide of a total 98 amino acids with 20 to 30% identity to other human CC chemokines. We termed this novel chemokine from EBI1-Ligand Chemokine as ELC (see below). The ELC mRNA was most strongly expressed in the thymus and lymph nodes. Recombinant ELC protein was expressed as a fusion protein with the Flag tag (ELC-Flag). For receptor-binding assays, recombinant ELC protein fused with the secreted form of alkaline phosphatase (SEAP) was used. By stably expressing five CC chemokine receptors (CCR1 to 5) and five orphan receptors, ELC-SEAP was found to bind specifically to an orphan receptor EBI1. Only ELC-Flag, but not MCP-1, MCP-2, MCP-3, eotaxin, MIP-1alpha, MIP-1beta, RANTES (regulated on activation normal T cell expressed and secreted), thymus and activation-regulated chemokine (TARC), or liver and activation-regulated chemokine (LARC), competed with ELC-SEAP for EBI1. ELC-Flag-induced transient calcium mobilization and chemotactic responses in EBI1-transfected cells. ELC-Flag also induced chemotaxis in HUT78 cells expressing endogenous EBI1 at high levels. By somatic hybrid and radiation hybrid analyses, the gene for ELC (SCYA19) was mapped to chromosome 9p13 instead of chromosome 17q11.2 where the genes for CC chemokines are clustered. Taken together, ELC is a highly specific ligand for EBI1, which is known to be expressed in activated B and T lymphocytes and strongly up-regulated in B cells infected with Epstein-Barr virus and T cells infected with herpesvirus 6 or 7. ELC and EBI1 may thus play roles in migration and homing of normal lymphocytes, as well as in pathophysiology of lymphocytes infected with these herpesviruses. We propose EBI1 to be designated as CCR7.