Expression Patterns Of Chemokine Receptors Research Articles

The characterization of chemokine production and chemokine receptor expression reveals possible functional cross-talks in AML blasts with monocytic differentiation.

The mechanisms regulating the trafficking of leukemic myeloid blasts are poorly understood. A differential expression of chemokines and chemokine receptors might account for some aspects of the pattern of invasion and accumulation of leukemic cells. We aimed at defining the pattern of chemokine and chemokine receptor expression of acute myeloid leukemia (AML) blasts in comparison with their putative normal cell counterparts. Twenty-five cases of AML were analyzed by flow cytometry for the expression of several chemokine receptors and by RT-PCR for the expression of relevant chemokines. For selected chemokines, the production was confirmed by ELISA. AML blasts were also assessed for their migration capacity in response to autologous supernatants and recombinant chemokines. Undifferentiated AML (MO-M1 and some M2) express only CXCR4 on their surface and produce mainly inflammatory chemokines, resembling normal CD34+ progenitors. More differentiated AML (M4-M5 and some M2) have a more diversified receptor repertoire and, besides CXCR4, express the receptors for inflammatory chemokines and produce both constitutive and inflammatory chemokines, resembling resting and activated monocytes. In particular, M4-M5 blasts produce MCP-1 and MIP-3alpha and also express their specific receptors (CCR2 and, to a lesser extent, CCR6) and migrate in vitro in response to MCP-1 and MIP-3alpha and to their own supernatant. A significant correlation between extramedullary involvement and coexpression of MCP-1/CCR2 was found. These data suggest that chemokines and their receptors segregate within the different FAB subtypes and, by allowing cross-talk among members of the malignant clone, might help to explain some aspects of the pattern of invasion in AML with monocytic differentiation.

Chemokines and matrix metalloproteinase-9 in leukocyte recruitment to the central nervous system

Chemokines and matrix metalloproteinases (MMPs) play key roles in leukocyte migration across the blood–brain barrier (BBB) in infectious and inflammatory diseases, including multiple sclerosis (MS). In MS some chemokine receptors are expressed by an increased percentage of T cells in blood, the CSF concentration of chemokine ligands for these receptors is increased, and there is accumulation of T cells expressing relevant chemokine receptors in CSF and in the CNS parenchyma. Chemokine receptor expression patterns appear to reflect disease activity and disease stage in MS. MMPs are constitutively expressed or induced by proinflammatory cytokines and chemokines in leukocytes and CNS-resident cells. Several MMPs are expressed in MS plaques, and the CSF concentration of MMP-9 is increased in MS. The CSF concentration of MMP-9 may reflect disease activity in MS, and the CSF concentration of MMP-9 is higher in patients carrying the MS-associated HLA type DRB1 ∗1501. We review how chemokines and MMP-9 may be involved in the pathogenesis of MS by controlling leukocyte migration between different functional compartments. Measuring expression of these molecules may find use as surrogate markers of disease activity in MS, and interfering with their function holds promise as a novel therapeutic strategy in MS.

The fractalkine receptor CX3CR1 is a key mediator of atherogenesis.

Recruitment of circulating monocytes to the arterial intima contributes to the formation of atherosclerotic lesions and may participate in their destabilization. Leukocyte emigration from blood into tissues is mediated by multiple adhesion molecules and chemokines, which orchestrate specific steps of emigration and regulate preferential recruitment of different leukocytes depending on their expression patterns of chemokine receptors. Over the last several years, a number of adhesion molecules, including VCAM-1, P-selectin and ICAM-1, the chemokines MCP-1 (also known as CCL2) and IL-8 (also known as CXCL8), and their respective receptors CCR2 and CXCR2, have been functionally implicated in atherosclerosis. Two studies — one recently published in the JCI (1), and the second reported in this issue (2) — expand this list to include the chemokine receptor CX3CR1, the receptor for fractalkine (also known as CX3CL1).

Kinetics and expression patterns of chemokine receptors in human CD4+ T lymphocytes primed by myeloid or plasmacytoid dendritic cells.

We investigated the kinetics of expression of 12 chemoattractant receptors as a function of cell division following priming of human naive CD4+ T cells by different populations of dendritic cells (DC) and under conditions favoring Th1 or Th2 differentiation. Two chemokine receptors, CXCR3 and CXCR5, were rapidly up-regulated following T cell activation by either monocyte-derived DC, myeloid DC (mDC) or plasmacytoid DC (pDC). While CXCR5 expression was transient, expression of CXCR3 at advanced cell divisions was dependent on differentiation, being expressed at high levels on Th1 cells. Several other receptors (CCR2, CCR3, CCR4, CCR5, CXCR6 and CRTh2) were acquired progressively as a function of cell division and in a fashion that was influenced by polarizing cytokines. The Th2-associated chemoattractant receptors CRTh2 and CCR3 were up-regulated with slower kinetics compared to the Th1-associated receptors CXCR3 and CXCR6, consistent with a different kinetics and efficiency of polarization. Moreover, CCR4 and CXCR6 were preferentially induced in T cells activated by mDC and pDC, respectively. Finally, CXCR5 and CCR7 were also rapidly and transiently up-regulated in memory T cells following TCR stimulation. These results indicate a complex chemokine receptor regulation dependent on both T cell activation and differentiation state. In addition, they reveal the existence of DC-specific cues for the regulation of T cell migratory capacity.

Systemic chemokine and chemokine receptor responses are divergent in allergic versus non-allergic humans.

T(h)1- and T(h)2-polarized human T cell clones display distinct patterns of chemokine receptor expression and selective chemokine responsiveness in vitro. We hypothesized that natural exposure to environmental grass pollen would induce differential systemic chemokine and chemokine receptor expression patterns in individuals with allergic rhinitis compared to healthy controls with type 2- and type 1-dominated responses to allergen respectively. To this end, we compared chemokine receptor expression on peripheral blood T cells directly ex vivo and plasma chemokine levels between these two groups of study participants prior to and during the grass pollen season. T(h)1-associated CXC chemokine receptor (CXCR) 3 was strongly expressed on >50% CD4(+)/CD45RO(+) cells of all subjects. When examined longitudinally, CXCR3 expression increased over the grass pollen season (P < 0.0001), solely in non-allergic subjects. In contrast, for both allergic and non-allergic subjects, CC chemokine receptor (CCR) 5 (T(h)1-associated) and CCR3 (T(h)2-associated) were weakly expressed on <10% of CD4(+)/CD45RO(+) cells both prior to and during the grass pollen season. Type 1 chemokines CXC chemokine ligand (CXCL) 9 and CXCL10 (monokine induced by IFN-gamma and IFN-gamma-inducible protein of 10 kDa: CXCR3 ligands), and type 2 chemokines CC chemokine ligand (CCL) 11 (eotaxin: CCR3 ligand), CCL17 (thymus and activation-regulated chemokine: CCR4 ligand) and CCL22 (monocyte-derived chemokine: CCR4 ligand) were readily detectable in the plasma of most participants. Systemic CXCL9 levels decreased from pre- to grass pollen season in allergics (P < 0.05), whereas CCL17 decreased in non-allergics (P < 0.05) over the same period. Taken together, these longitudinal data suggest a systemic shift to more intensely type 1-dominated responses in non-allergic individuals and, conversely, to more type 2-dominated responses in allergic individuals upon natural re-exposure to grass pollen.

MHC class II engagement by its ligand LAG-3 (CD223) leads to a distinct pattern of chemokine and chemokine receptor expression by human dendritic cells

Upon stimulation by infectious agent products, dendritic cells (DC) become activated, express high levels of class I and class II antigens, CD80, CD86 and CD83 and migrate to secondary lymphoid organs where they can prime naive CD4-helper and CD8-cytotoxic T-cells. Cognate CD4 + T-cell help mediated by CD40L along with DC stimulation with another T-cell effector molecule, termed lymphocyte activated gene-3 (LAG-3 or CD223, a ligand for MHC class II) have been shown to induce this maturation process. Both CD40L and LAG-3 have been used as vaccine adjuvants to induce CTL and CD4 Th1 responses. Here, we studied the effect of a soluble LAG-3Ig molecule on the chemokine and chemokine receptor profile of human immature monocyte-derived DC. LAG-3Ig, unlike CD40L, induced an inflammatory signal in terms of IL-8 and MIP-1α/CCL3 production and, in contrast to LPS, induced production of chemokines (MDC/CCL22 and TARC/CCL17) known to direct the migration of maturing DC to lymph nodes. In LAG-3-matured DC, surface expression of CCR5 (a receptor for MIP-1α/CCL3) was down-regulated and CCR7 (a receptor for MIP-3β and SLC) was up-regulated. However, LAG-3-matured, but not LPS- or CD40L-matured DC retained their capacity to migrate in chemotaxis chambers and to respond to MIP-1α. Altogether, these data represent the first evidence that MHC class II signaling may affect DC migration to secondary lymphoid tissues.

Rapid leukocyte integrin activation by chemokines.

Chemokines control selective targeting of circulating leukocytes to the microvasculature by triggering inside-out signal transduction pathways leading to integrin-dependent adhesion. Integrin activation by chemokines is very rapid, is downmodulated within minutes and appears to involve both enhanced heterodimer lateral mobility on the plasma membrane, facilitating encounters with dispersed ligand, as well as induction of a high-affinity state. These two modalities of integrin activation by chemokines involve distinct signaling pathways in the cell, yet complement each other functionally, allowing binding of rolling cells under conditions of low as well as high ligand density. Recent data show that chemokines generate both pro- and anti-adhesive intracellular signaling events, whose equilibrium is likely to be relevant to the kinetics of adhesion and de-adhesion, and to cell movement during diapedesis and chemotaxis. Importantly, chemokines utilize different signaling mechanisms to modulate the activity of distinct integrin subtypes. These recent advances suggest that chemokines may regulate adhesive responses of immune cells based not only on patterns of chemokine receptor expression, but also on variable signaling pathways that can modulate the pro-adhesive responses of leukocytes as a function of their differentiated state, and of the local microenvironment.

Chemokine receptor expression on MBP-reactive T cells: CXCR6 is a marker of IFNγ-producing effector cells

Cytokine-polarized T cells have distinct chemokine receptor (CKR) expression patterns associated with their cytokine secretion profiles. In order to investigate this paradigm in autoreactive human T cells, we have determined the CKR expression pattern of myelin basic protein (MBP)-reactive T cell lines (TCL) and compared these profiles to those of TCL-generated in response to tetanus toxoid (TT). Expression of CXCR6 and CXCR3 on TCL was significantly positively correlated with IFNγ, and inversely correlated with IL-5 production. TT TCL had significantly higher expression of CCR7 −/CD45RA − T effector memory (Tem) cells than MBP TCL. However, in MBP-specific TCL, CXCR6 was found to be the best marker of conversion to the Tem phenotype. CXCR6 and CXCR3 are likely to be important in the migration of effector memory T cells in Th1-mediated inflammatory diseases such as multiple sclerosis (MS).

Modulation of chemokine receptor expression and chemotactic responsiveness during differentiation of human naive T cells into Th1 or Th2 cells

Chemokines and their receptors direct movements and encounters of lymphocytes and professional APC into specific microenvironments of lymphoid tissues. Chemokine receptors such as CCR7, CXCR5 and CCR4 that are differentially expressed and modulated in distinct subsets of T cells contribute to establish functionally and spatially segregated microenvironments within secondary lymphoid tissues where T cell activation and differentiation occur. Here, we have explored the modulation of CCR7, CCR4, CCR8 and CXCR5 expression and chemotactic responsiveness to their ligands during commitment of human naive T cells along the Th1 or Th2 differentiation pathway in vitro. Our results document that activation of human naive T cells and differentiation in Th1 or Th2 cells result in progressive down-modulation of CCR7 expression and CCL19 responsiveness. By contrast, expression of CCR4 and responsiveness to CCL22 is rapidly induced at the early stages of both Th1/Th2 cell development. However, while CCR4 expression is further up-regulated upon differentiation into Th2 cells, it is lost on fully differentiated Th1 cells. CCR8 is detected at later time points than CCR4 and exclusively on differentiated Th2 cells as revealed by analysis of mRNA expression and responsiveness to CCL1. Expression of CXCR5 is transiently induced at the early stages of Th cell differentiation, but with distinct kinetics in developing Th1 and Th2 cells. Analysis of human tonsillar CD4(+) T cells reveals a consistent pattern of chemotactic responsiveness and chemokine receptor expression in distinct transitional stages of human T cell activation and differentiation in vivo.

Chemokines and chemokine receptors in inflammatory demyelinating neuropathies: a central role for IP‐10

Inflammatory cell recruitment is an important step in the pathogenesis of autoimmune demyelinating diseases of the PNS. Chemokines might play a critical role in promoting leucocyte entry into the nervous system during immune-mediated inflammation. Here, we report the expression pattern of the chemokine receptors CCR-1, CCR-2, CCR-4, CCR-5 and CXCR-3 in sural nerve biopsies obtained from patients with classical Guillain-Barré syndrome (acute inflammatory demyelinating polyradiculoneuropathy), chronic inflammatory demyelinating polyradiculoneuropathy and various non-inflammatory neuropathies. A consistent chemokine receptor expression pattern was immunohistochemically detected in inflammatory demyelinating neuropathies and quantitation of labelled mononuclear cells revealed significantly elevated cell counts compared with controls. CCR-1 and CCR-5 were primarily expressed by endoneurial macrophages, whereas CCR-2, CCR-4 and CXCR-3 could be localized to invading T lymphocytes. Quantitative analysis revealed that CXCR-3 was expressed at highest numbers by infiltrating T cells compared with the other receptors. Thus, expression and distribution of CXCR-3 suggest a specific role of this receptor in chemokine-mediated lymphocyte traffic into the inflamed PNS tissue. Therefore, we further analysed the expression of its ligands interferon-gamma-inducible protein of 10 kDa (IP-10) and monokine induced by interferon-gamma (Mig). Significantly increased levels of IP-10 could be measured in the CSF of patients with inflammatory neuropathies, whereas no differences were observable for Mig. In situ hybridization for IP-10 mRNA mirrored the distribution of the cognate receptor within the inflamed PNS, and delineated endothelial cells as the primary cellular source of IP-10. Our results imply a pathogenic role for specific chemokine receptors and IP-10 in the genesis of inflammatory demyelinating neuropathies.

EXPRESSION AND FUNCTIONAL ANALYSIS OF CHEMOKINE RECEPTORS IN HUMAN PERIPHERAL BLOOD LEUKOCYTE POPULATIONS

Emerging evidence indicates that chemokine receptor expression patterns are critical in determining the spectrum of action of the chemokines. We have analysed the expression patterns of 17 chemokine receptors and two orphan chemokine receptor-like genes in various freshly prepared human peripheral blood leucocyte populations, including neutrophils, lymphocytes, and naı̈ve and differentiated monocytes using real-time quantitative polymerase chain reaction (TaqMan®). This is the first comprehensive study of chemokine receptor expression in such a wide variety of cell types. Human peripheral blood leukocyte populations were found to express a wide range of chemokine receptors that varies depending on cell type and differentiation state. Novel expression patterns of certain chemokine receptors were seen during our analysis. For example, the orphan chemokine receptor HCR was expressed at very high levels by both primary neutrophils and primary monocytes, and was further upregulated on neutrophil activation and during monocyte to macrophage differentiation. When neutrophil calcium transients were measured in response to a panel of 30 different chemokines the results clearly correlated with the chemokine receptor expression profile. For example strong calcium responses were seen in neutrophils following stimulation with the CXCR1 and CXCR2 ligands, interleukin (IL-)8, GCP-2 and Gro-β. These data have implications for the study of the functional responses of leukocytes to external stimuli and will aid in our understanding of general leukocyte biology.

Expression pattern of CXCR3, CXCR4, and CCR3 chemokine receptors in the developing human brain.

Chemokine receptors are essential components of the immune and central nervous systems, but little is known about their distribution during development. We evaluated the distribution of 3 chemokine receptors: CXCR3, CXCR4, and CCR3 in the human developing brain. Of these, CXCR3 was the only receptor expressed in fetal brain at 26 wk of gestation and its expression was restricted to glial cells, endothelial cells, and the choroid plexus. Neuronal staining was only seen at term in the Purkinje cells of the cerebellum. CCR3 appeared only at term in both neurons and glial cells. The expression pattern of these 2 receptors in the late gestation and term resembled that of adults. CXCR4 could not be detected in the fetal brain on neurons nor on glial cells. By examining pediatric cases, we determined that CXCR4 expression commences sometimes between 3.5 and 4.5 yr. Two of the chemokine receptors examined, CCR3 and CXCR4, can be used as co-receptor together with CD4 for HIV entry, but neither was expressed during the second trimester of pregnancy. Our findings suggest that it is unlikely that CCR3 or CXCR4 play a major role in HIV-1 transmission in the fetal brain before 37 wk of gestation.

Expression pattern of T-cell–associated chemokine receptors and their chemokines correlates with specific subtypes of T-cell non-Hodgkin lymphoma

AbstractChemokine receptors mediate the migration of lymphocytes through the binding of soluble ligands, and their expression is differentially regulated in lymphocyte subsets. The pattern of chemokine receptor expression in T-cell non-Hodgkin lymphoma has not been previously studied. Using a panel of mouse monoclonal antibodies, we studied the immunohistochemical expression of the Th1-associated chemokine receptor CXCR3 in 141 patients with T-cell lymphoma, and we studied the receptors CCR4 and CCR5 and some of their ligands in a subset of these tumors. Expression of CXCR3 was typical of the smaller T cells in angioimmunoblastic lymphoma (15 of 18 patients), angiocentric lymphoma (3 of 3 patients), histiocyte-rich tumors (4 of 5 patients), and unspecified T-cell lymphomas (17 of 39 patients). CXCR3 expression was seen in only 1 of 15 patients with anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma. In contrast, all ALK-positive tumors showed diffuse reactivity for the Th2-associated receptor CCR4 (5 of 5 patients). CCR4 expression was also a consistent feature of the large-cell transformation of mycosis fungoides. CCR5 expression showed no consistent association with any T-cell tumor type. The chemokines Mig (CXCR3 ligand), TARC (CCR4 ligand), and MCP-2 (CCR5 ligand) were detected in intratumoral blood vessels and histiocytes. Mig was also coexpressed by a subset of CXCR3-positive tumor cells in 6 of 20 lymphomas. MCP-2 was highly expressed in stromal cells in 3 patients with nodal involvement by cutaneous T-cell lymphoma. As with normal T-cell subsets, we demonstrated that there is frequent differential expression of chemokine receptors in T-cell tumors, which may explain, in part, the distinctive patterns of spread in different tumor subtypes.

Expression pattern of T-cell–associated chemokine receptors and their chemokines correlates with specific subtypes of T-cell non-Hodgkin lymphoma

Chemokine receptors mediate the migration of lymphocytes through the binding of soluble ligands, and their expression is differentially regulated in lymphocyte subsets. The pattern of chemokine receptor expression in T-cell non-Hodgkin lymphoma has not been previously studied. Using a panel of mouse monoclonal antibodies, we studied the immunohistochemical expression of the Th1-associated chemokine receptor CXCR3 in 141 patients with T-cell lymphoma, and we studied the receptors CCR4 and CCR5 and some of their ligands in a subset of these tumors. Expression of CXCR3 was typical of the smaller T cells in angioimmunoblastic lymphoma (15 of 18 patients), angiocentric lymphoma (3 of 3 patients), histiocyte-rich tumors (4 of 5 patients), and unspecified T-cell lymphomas (17 of 39 patients). CXCR3 expression was seen in only 1 of 15 patients with anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma. In contrast, all ALK-positive tumors showed diffuse reactivity for the Th2-associated receptor CCR4 (5 of 5 patients). CCR4 expression was also a consistent feature of the large-cell transformation of mycosis fungoides. CCR5 expression showed no consistent association with any T-cell tumor type. The chemokines Mig (CXCR3 ligand), TARC (CCR4 ligand), and MCP-2 (CCR5 ligand) were detected in intratumoral blood vessels and histiocytes. Mig was also coexpressed by a subset of CXCR3-positive tumor cells in 6 of 20 lymphomas. MCP-2 was highly expressed in stromal cells in 3 patients with nodal involvement by cutaneous T-cell lymphoma. As with normal T-cell subsets, we demonstrated that there is frequent differential expression of chemokine receptors in T-cell tumors, which may explain, in part, the distinctive patterns of spread in different tumor subtypes.

Expression of multiple functional chemokine receptors and monocyte chemoattractant protein-1 in human neurons

Functional chemokine receptors and chemokines are expressed by glial cells within the CNS, though relatively little is known about the patterns of neuronal chemokine receptor expression and function. We developed monoclonal antibodies to the CCR1, CCR2, CCR3, CCR6, CXCR2, CXCR3 and CXCR4 chemokine receptors to study their expression in human fetal neurons cultured from brain tissue as well as the clonally derived NT2.N human neuronal cell line (NTera 2/cl.D1). Specific monoclonal antibody labeling demonstrated expression of CCR2, CXCR2, CXCR3 and CXCR4 on neurons from both sources. Co-labeling studies revealed strong expression of CXCR3 and CXCR4 on both dendritic and axonal processes, with a weaker expression of CXCR2 and CCR2. Reverse transcriptase–polymerase chain reaction analysis of pure NT2.N neurons confirmed RNA expression for CCR2, CXCR2, CXCR3 and CXCR4. No changes in the neuronal labeling pattern of chemokine receptor expression were noted when NT2.N neurons were grown on a supporting layer of astrocytes, again consistent with similar patterns seen in primary human fetal brain cultures. Analysis of single-cell calcium transients revealed a robust response to stromal derived factor-1α (CXCR4) and melanocyte growth-stimulating activity (CXCR2), and variable response to monocyte chemoattractant protein-1 (CCR2) or interferon-γ inducible protein-10 (CXCR3). Finally, we detected the release of monocyte chemoattractant protein-1 from pure cultures of NT2.N neurons, but not undifferentiated NT2 cells. These data indicate that individual neurons may not only co-express multiple functional chemokine receptors, but also that neurons themselves produce chemokines which may influence cellular function within the central nervous system.

Chemokine and chemokine receptor expression in a novel human mesangial cell line.

Chemokines are thought to play a pivotal role in mediating the selective migration of leukocytes into sites of tissue injury. The local production of chemokines by mesangial cells (MC) has been linked to inflammatory processes within the glomerulus. To study the chemokine biology of human MC, an immortalized human MC line was generated and then chemokine and chemokine receptor expression was examined in response to various proinflammatory stimuli. The results show that human MC have a specific and limited repertoire of chemokine expression. The stimulus-specific regulation of the chemokines monocyte chemoattractant protein- (MCP- 1), regulated upon activation, normal T cell expressed and secreted (RANTES), interleukin-8 (IL-8), and IP-10 was demonstrated using RNase protection assays. Transcripts for the chemokines MIP-1alpha, MIP-1beta, I-309, or lymphotactin could not be detected. The expression of CC chemokine receptors was investigated by reverse transcription-PCR and RNase protection assays. MC stimulated with interferon-gamma (IFN-gamma) expressed mRNA for the chemokine receptor CCR1. The expression could be further increased by activating the cells with a combination of tumor necrosis factor-a (TNF-alpha), IL-1beta, and IFN-gamma. Under these conditions, no mRNA for CCR2, CCR3, CCR4, CCR5, or CCR8 was detected. A comparison of the immortalized human mesangial cells with primary cells showed identical expression patterns of chemokine receptors. To demonstrate functional activity of chemokine receptors expressed by human MC, chemotaxis assays were performed. MC stimulated with a combination of TNF-alpha, IL-1beta, and IFN-gamma, but not unstimulated MC, migrated toward a RANTES gradient. Eotaxin did not enhance the migratory activity of human MC. In summary, a novel human mesangial cell line was established and the pattern of chemokine expression was examined. For the first time, the inducible expression of functionally active CCR1 by human MC was shown.

Chemokine receptors and their antagonists in allergic lung disease.

The trafficking and homing of leukocytes in normal homeostasis and in disease is under the control of a variety of cytokine and lipid mediators. One family of small cytokines particularly involved in inflammation which has been identified is the chemokine family. Their action is mediated by a large superfamily of seven transmembrane spanning G-protein coupled receptors. One of the hopes in this field has been there may be selectivity in terms of which cells are recruited to sites of inflammation by virtue of their chemokine receptor expression pattern. This means that it may be possible to find antagonists of chemokine receptors that can selectively down regulate certain cell type recruitment, without provoking a generalized immunosuppression. In this review, we discuss the current state of understanding of the chemokine receptor field. The therapeutic potential of this field can be judged from recent data on the use of protein chemokine antagonists in allergic disease. The data so far obtained in animal studies point to the potential clinical uses of this emerging class of therapeutic agents.

Cutting Edge: Selective Up-Regulation of Chemokine Receptors CCR4 and CCR8 upon Activation of Polarized Human Type 2 Th Cells

AbstractPolarized Th1 and Th2 cells differentially express adhesion molecules and chemokine receptors, endowing these cells with distinct tissue homing capabilities. Here we report that, in contrast to other chemokine receptors, the expression of CCR4 and CCR8 on Th2 cells is transiently increased following TCR and CD28 engagement. IL-4 is not required for this activation-induced up-regulation of CCR4 and CCR8. In accordance with receptor expression, the response of Th2 cells to I-309 (CCR8 ligand) and thymus- and activation-regulated chemokine (CCR4 and CCR8 ligand) is enhanced upon activation. Moreover, activated Th1 cells up-regulate CCR4 expression and functional responsiveness to thymus- and activation-regulated chemokine. Analysis of polarized subsets of CD8+ T cells reveals a similar pattern of chemokine receptor expression and modulation of responsiveness. Taken together, these findings suggest that an up-regulation of CCR4 and CCR8 following Ag encounter may contribute to the proper positioning of activated T cells within sites of antigenic challenge and/or specialized areas of lymphoid tissues.

Chemokine receptors in HIV-1 infection of the central nervous system

Several members of the chemokine receptor are used as coreceptors for HIV-1 infection in the central nervous system (CNS). CCR5 and CCR3 are coreceptors together with CD4 for HIV-1 infection of microglia, the major target for HIV-1 infection in the CNS. Microglia express CXCR4, but their infection by HIV-1 viruses that use only CXCR4 as a coreceptor is relatively inefficient. CXCR4 is also expressed in subpopulations of neurons that are resistant to HIV-1 infection. Additional orphan chemokine receptors that can mediate HIV-1 or SIV entry are expressed in the brain or neurally-derived cell lines, but their role in CNS infection has not been defined. The pattern of chemokine receptor expression in the brain is likely to determine the tropism of HIV-1 for particular CNS target cells and to impact inflammatory and degenerative mechanisms associated with CNS infection.

Effect of a CC chemokine receptor antagonist on collagen induced arthritis in DBA/1 mice

Chemokines are small proteins that selectively activate and recruit leukocytes to sites of inflammation. Several of them, including the CC chemokines RANTES, MIP-1 α, MIP-1 β, MCP-1, and the CXC chemokines IL-8, GRO- α, ENA-78 have been identified in rheumatoid synovium, implicating a potential role for these molecules in rheumatoid arthritis. We have investigated the expression patterns of CC chemokine receptors in the joints of mice with collagen-induced arthritis, a model for human rheumatoid arthritis. In addition, we have investigated the incidence and severity of arthritis in mice receiving administration of MetRANTES, a modified chemokine which is a nanomolar antagonist of certain CC chemokine receptors. The mRNA expression pattern of the chemokines and their receptors in the joints of arthritic mice was investigated using reverse transcriptase-PCR and in situ hybridization. An upregulation of the CC chemokine receptors mCCR1, mCCR2, mCCR3 and mCCR5 was found in the joints from arthritic mice, compared to control animals. In addition, injections of MetRANTES reduced the incidence of disease in a dose dependent manner. Furthermore, in MetRANTES-treated mice that did develop arthritis a significantly lower severity of disease was observed compared with control animals. Our data clearly demonstrate a role for CC chemokines and their receptors in inflammatory joint destruction and support the use of chemokine receptor antagonists as potential tools to control inflammatory diseases such as rheumatoid arthritis.