Dispensable role of chemokine receptors in migration of mycobacterial antigen-specific CD4+ T cells into Mycobacterium-infected lung

Mycobacterial antigen-specific CD4⁺ Th1 cells have pivotal role in protective immunity against mycobacterial infections including pulmonary tuberculosis. In the course of the infection, Th1 cells differentiate in the lung-draining lymph nodes and migrate into the infected lung. Chemokine receptors on T cells are involved in T cell migration into the intestine and skin. However, role of chemokine receptors in the migration of CD4⁺ T cells into the lung is not yet established. To address the issue, the role of chemokine receptors in T cell migration into the mycobacteria-infected lung was analyzed using mycobacterial Ag85B peptide 25-specific T cell receptor-transgenic (P25) CD4⁺ T cells. The P25 T cells in the Mycobacterium bovis BCG-infected lung and lung-draining mediastinal lymph node expressed chemokine receptors CCR5, CCR6, CXCR3 and CXCR5 which bind chemokines expressed by the BCG-infected lung. To further analyze the role of the chemokine receptors in the migration of the BCG-primed P25 T cells into the lung or mediastinal lymph node, the P25 T cells were adoptively transferred into the BCG-infected wild type mice, and their migration into the lung was monitored. Unexpectedly, blocking of chemokine receptor function with pertussis toxin, a G-protein inhibitor, failed to suppress migration of the T cells into the infected lung although the treatment completely blocked migration of the mediastinal lymph node P25 T cells into the recipient lymph node. The results suggest that interaction of chemokine receptors on mycobacterial antigen-specific Th1 cells with chemokines is dispensable in their migration into the mycobacteria-infected lung.     

Differential migration behavior and chemokine production by myeloid and plasmacytoid dendritic cells

The existence of dendritic cell (DC) subsets is firmly established, but their trafficking properties are still largely unknown. We have indicated that myeloid dendritic cells (M-DCs) and plasmacytoid dendritic cells (P-DCs) isolated from human blood differ widely in the capacity to migrate to chemotactic stimuli. The pattern of chemokine receptors expressed ex vivo by both subsets is similar, but P-DCs display, compared with M-DCs, higher levels of CC chemokine receptor (CCR)5, CCR7, and CXCR3. Intriguingly, most chemokine receptors of P-DCs, in particular those specific for inflammatory chemokines and classical chemotactic agonists, are not functional in circulating cells. Following maturation induced by cluster designation (CD)40 ligation, the receptors for inflammatory chemokines are downregulated and CCR7 on P-DCs becomes coupled to migration. The drastically impaired capacity of blood P-DCs to migrate in response to inflammatory chemotactic signals contrasts with the response to lymph node-homing chemokines, indicating a propensity to migrate to secondary lymphoid organs rather than to sites of inflammation. The distinct migration behavior of DC subsets is accompanied by a different profile of chemokine production. In contrast to the high production by M-DCs, the homeostatic CC chemokine ligand (CCL)17/ thymus- and activation-regulated chemokine (TARC) is not produced by PDCs in response to any stimulus tested and their production of CCL22/MDC is minimal, if any, compared with M-DCs. Thus, stimulated M-DCs, but not P-DCs, are able to produce high levels of chemokines recruiting T-helper 2 cells (Th2) and T-regulatory cells. Conversely, the proinflammatory chemokine CCL3/macrophage inflammatory protein (MIP)-1 is predominantly produced by P-DCs. Therefore, P-DCs appear to produce preferentially proinflammatory chemokines, but to respond selectively to homeostatic ones, whereas the reverse is true for M-DCs, highlighting not only the different migratory properties of these DC subsets, but also their capacity to recruit different cell types at inflammation sites.     

Cutaneous lymphoma and chemokine

The expression pattern of chemokines and chemokine receptors is specific to certain organs and cells. Therefore, chemokines are important to elucidate the mechanism of organ-specific human diseases such as cutaneous lymphoma, characterized by proliferation of clonally expanded lymphocytes in skin without detectable systemic involvement. The most popular type of cutaneous lymphoma is T cell lymphoma, including mycosis fungoides and Sezary syndrome. We have reported that CCL17, CCL27, CCL11, and CCL26 are involved in progression of these diseases. The above chemokines are highly expressed in the lesional skin and serum levels of the chemokines are elevated as the disease progressed. Moreover, CXCL9 and CXCL10 are associated with epidermotropism of tumor cells, CCL21 is important for tumor invasion to lymph nodes, and CXCL12 may explain downregulation of CD26 on the cell surface. CXCL13 expression in lymphoid follicular formation in skin and CCR3 expression on tumor cells in CD30(+) lymphoproliferative disorders are also discussed. Biologics targeting chemokines and their receptors are promising strategies for cutaneous lymphoma. Indeed, humanized anti-CCR4 monoclonal antibody showed potent antitumor activity against CCR4(+) lymphoma cells both in vitro and ex vivo. This antibody may also be useful for allergic diseases such as hay fever. Further study on chemokines and chemokine receptors will be helpful for new classification of cutaneous lymphoma, elucidation of pathogenesis, and development of new therapeutic strategies.     

Impaired CD4 and CD8 T cell phenotype and reduced chemokine secretion in recent-onset type 1 diabetic children

Although the role of the T cell-mediated autoimmune reaction in type 1 diabetes (T1D) is conclusive, studies including data from human circulating CD4(+) and CD8(+) lymphocytes subsets during the disease onset and posterior development are scarce. Further, chemokines and chemokine receptors are key players in the migration of pathogenic T cells into the islets of non-obese diabetic mice developing T1D, but few studies have investigated these markers in human T1D patients. We studied the expression of T helper 1 (Th1)- and Th2-associated chemokine receptors, and the two isoforms of CD45 leucocyte antigen on CD4(+) and CD8(+) lymphocytes from T1D and healthy children, as well as the secretion of chemokines in cell supernatants in peripheral blood mononuclear cells. Our results showed increased expression of CCR7 and CD45RA and reduced CD45RO on CD8(+) cells among recent-onset T1D patients. The percentages of CD4(+) cells expressing CXC chemokine receptor 3 (CXCR3), CXCR6 and CCR5, and the secretion of interferon-gamma-induced protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta was lower among diabetics. Low expression of Th1-associated receptors and secretion of chemokines, together with an increased amount of CD8(+) cells expressing CD45RA and CCR7 in T1D patients therefore might represent suboptimal Th function in T1D, leading to impaired T cytotoxic responses or alternatively reflect a selective recruitment of Th1 cells into the pancreas.     

Selective human endothelial cell activation by chemokines as a guide to cell homing

An original model of organo-specific, immortalized and stabilized endothelial cell lines was used to delineate the part played by some chemokines (CCL21, CX3CL1, CCL5 and CXCL12) and their receptors in endothelium organo-specificity. Chemokine receptor expression and chemokine presentation were investigated on organo-specific human endothelial cell lines. Although the chemokines showed distinct binding patterns for the various endothelial cell lines, these were not correlated with the expression of the corresponding receptors (CX3CR1, CXCR4, CCR5 and CCR7). Experiments with CCL21 on peripheral lymph node endothelial cells demonstrated that the chemokine did not co-localize with its receptor but was associated with extracellular matrix components. The specific activity of chemokines was clearly shown to be related to the endothelial cell origin. Indeed, CX3CL1 and CCL21 promoted lymphocyte recruitment by endothelial cells from the appendix and peripheral lymph nodes, respectively, while CX3CL1 pro-angiogenic activity was restricted to endothelial cells from the appendix and skin. The high specificity of the chemokine/endothelium interaction allowed the design of a direct in vitro endothelial cell targeting assay. This unique cellular model demonstrated a fundamental role for chemokines in conferring on the endothelium its organo-specificity and its potential for tissue targeting through the selective binding, presentation and activation properties of chemokines.     

The role of chemokines in the recruitment of lymphocytes to the liver

Chemokines direct leukocyte trafficking and positioning within tissues. They thus play critical roles in regulating immune responses and inflammation. The chemokine system is complex involving interactions between multiple chemokines and their receptors that operate in combinatorial cascades with adhesion molecules. The involvement of multiple chemokines and chemokine receptors in these processes brings flexibility and specificity to recruitment. The hepatic vascular bed is a unique low flow environment through which leukocyte are recruited to the liver during homeostatic immune surveillance and in response to infection or injury. The rate of leukocyte recruitment and the nature of cells recruited through the sinusoids in response to inflammatory signals will shape the severity of disease. At one end of the spectrum fulminant liver failure results from a rapid recruitment of leukocytes that leads to hepatocyte destruction and liver failure at the other diseases such as chronic hepatitis C infection may progress over many years from hepatitis to fibrosis and cirrhosis. Chronic hepatitis is charactezised by a T lymphocyte rich infiltrate and the nature and outcome of hepatitis will depend on the T cell subsets recruited, their activation and function within the liver. Different subsets of effector T cells have been described based on their secretion of cytokines and specific functions. These include Th1 and Th2 cells and more recently Th17 and Th9 cells which are associated with different types of immune response and which express distinct patterns of chemokine receptors that promote their recruitment under particular conditions. The effector function of these cells is balanced by the recruitment of regulatory T cells that are able to suppress antigen-specific effectors to allow resolution of immune responses and restoration of immune homeostasis. Understanding the signals that are responsible for recruiting different lymphocyte subsets to the liver will elucidate disease pathogenesis and open up new therapeutic approaches to modulate recruitment in favour of resolution rather than injury.     

Differential production of macrophage inflammatory protein 1gamma (MIP-1gamma), lymphotactin, and MIP-2 by CD4(+) Th subsets polarized in vitro and in vivo

Due to differential expression of chemokine receptors, the Th1 and Th2 subsets of CD4(+) T cells differ in their migratory responses to chemokines. These differences in the migration patterns are likely to play a role in the initiation and regulation of Th1 and Th2 immune responses, inflammatory processes, and T-cell-mediated pathology. In the present study we evaluated the role of activated Th cells as producers of chemokines. Three different sources of murine Th cells were used, i.e., long-term-cultured Th1 and Th2 cell clones, Th1 and Th2 cells differentiated from na?ve CD4(+) spleen and lymph node cells in vitro, and Th1 and Th2 subsets polarized in vivo using a murine experimental Leishmania major infection model. Following stimulation with anti-CD3, macrophage inflammatory protein 1gamma (MIP-1gamma) and lymphotactin were produced selectively by Th1 cells but not by Th2 cells. In contrast, only Th2 cells produced MIP-2. The possible biological relevance of these data was substantiated by the finding that in vivo-polarized Th1 cells, but not Th2 cells, produced MIP-1gamma and lymphotactin while in vivo-polarized Th2 cells secreted MIP-2. The above data demonstrate that Th1 and Th2 cells differ in their ability to produce chemokines, suggesting that Th1 and Th2 subsets differentially contribute to recruitment of cells into inflammatory foci.     

Switch in chemokine receptor expression upon TCR stimulation reveals novel homing potential for recently activated T cells.

When naive T lymphocytes are activated and differentiate into memory/effector cells, they down-regulate receptors for constitutive chemokines such as CXCR4 and CCR7 and acquire receptors for inflammatory chemokines such as CCR3, CCR5 and CXCR3, depending on the Th1/Th2 polarization. This switch in chemokine receptor usage leads to the acquisition of the capacity to migrate into inflamed tissues. Using RNase protection assays, staining with specific antibodies, and response to recombinant chemokines, we now show that following TCR stimulation, memory/effector T cells undergo a further and transient switch in receptor expression. CCR1, CCR2, CCR3, CCR5, CCR6 and CXCR3 are down-regulated within 6 h, while CCR7, CCR4, CCR8 and CXCR5 are up-regulated for 2 to 3 days. Up-regulation of CCR7 following TCR stimulation was observed also among resting peripheral blood T cells and required neither co-stimulation nor exogenous IL-2. On the other hand IL-2 down-regulated CXCR5, up-regulated CCR8 and facilitated the recovery of CCR3 and CCR5. Upon TCR stimulation, Th1 and Th2 cells produced comparable sets of chemokines, including RANTES, macrophage inflammatory protein-1beta, I-309, IL-8 and macrophage-derived chemokine, which may modulate surface chemokine receptors and contribute to cell recruitment at sites of antigenic recognition. Altogether these results show that following TCR stimulation effector/memory T cells transiently acquire responsiveness to constitutive chemokines. As a result, T cells that are activated in tissues may either recirculate to draining lymph nodes or migrate to nearby sites of organized ectopic lymphoid tissues.     

Changing responsiveness to chemokines allows medullary plasmablasts to leave lymph nodes

During T cell-dependent antibody responses lymph node B cells differentiate either to plasmablasts that grow in the medullary cords, or to blasts that proliferate in follicles forming germinal centers. Many plasmablasts differentiate to plasma cells locally, but some leave the medullary cords and migrate to downstream lymph nodes. To assess the basis for this migration, changes in the responsiveness of B cells to a range of chemokines have been studied as they differentiate. Naive B cells express high levels of CCR6, CCR7, CXCR4 and CXCR5. When activated B cells grow in follicles the expression of these chemokine receptors and the responsiveness to the respective chemokines is retained. During the extrafollicular response, plasmablast expression of CXCR5 and responsiveness to B-lymphocyte chemoattractant (CXCR5) as well as to secondary lymphoid tissue chemokine (CCR7) and stromal cell-derived factor (SDF)-1 (CXCR4) are lost while a weak response towards the CCR6 chemokine LARC is maintained. Despite losing responsiveness to SDF-1, extrafollicular plasmablasts still express high levels of CXCR4 on the cell surface. These results suggest that the combined loss of chemokine receptor expression and of chemokine responsiveness may be a necessary prerequisite for cells to migrate to the medullary cords and subsequently enter the efferent lymph.     

Targeting T cell responses by selective chemokine receptor expression

Immune responses require the orchestrated migration of T cells throughout the body. Conventional CD4+ and CD8+ alphabeta T cells undergo clonal expansion in the secondary lymphoid tissues, during which they are programmed to migrate into specific non-lymphoid tissues and other lymphoid effector sites such as B cell follicles. By contrast, T cell populations expressing receptors with limited diversity (i.e. gammadelta T cells and NK T cells) appear to be preprogrammed to localize in non-lymphoid tissues where they monitor tissue integrity or serve regulatory functions. By promoting chemotaxis and integrin activation, chemokines and their receptors (in conjunction with surface adhesion molecules) control these T cell homing events. Thus, expression of chemokine receptors defines T cells with tropism for particular tissues and/or microenvironments, and identifies T cell subsets with distinct functional properties.     

The roles of cytokine receptors in diseases

Cytokines are produced by various types of cells and have profound effects on the regulation of immune reactions, hematopoiesis, and inflammation. Herein, we will discuss the pathophysiological relevance of cytokine receptor expression, particularly focusing on chemokine receptor expression. Chemokines are cytokines with 4 cysteines at the well-conserved positions and exhibit potent chemotactic activities for various types of leukocytes. To date, accumulating evidence has indicated the potential involvement of these chemokines in inflammatory reactions through regulating inflammatory cell infiltration. Moreover, several lines of evidence demonstrate that different sets of chemokine receptors are expressed by T helper type 1 (Th1) and Th2 cells and that Th1 and Th2 cells respond to distinct sets of chemokines. These observations establish the essential roles of chemokines in helper T lymphocyte migration in vivo. Furthermore, several chemokine receptors are utilized as co-factors for human immunodeficiency virus entry and mutation in one chemokine receptor confers marked resistance to HIV infection. Therefore, the determination of chemokine receptors may provide invaluable information on the immune status and susceptibility to HIV infection.     

Inflammatory chemokines and their receptors in human visceral leishmaniasis: Gene expression profile in peripheral blood,splenic cellular sources and their impact on trafficking of inflammatory cells

Chemokines play an important role in determining cellular composition at inflammatory sites, and as such, influence disease outcome. In this study, we investigated the expression profile and splenic cellular source of various inflammatory chemokines and their receptors in human visceral leishmaniasis (VL). The expression of chemokines or their receptors was measured at the gene and protein level by employing real time qPCR and a cytometric bead array assay, respectively. In addition, the cellular source of chemokines and their receptors in the spleen was identified employing gene expression analyses in sequentially selected cell subsets. We identified elevated expression of CXCL10, CXCL9, CXCL8, and decreased CCL2 from VL patients. Further, we found reduced expression of the chemokine receptors CXCR1, CXCR2, CXCR3 and CCR2, but increased expression of CCR7 on VL PBMC, compared to endemic healthy controls. Additionally, splenic monocytes were found to be the major source of CXCL10, CXCL9 and CCR2, whereas T cells were the main source of CXCR3 and CCR7. We also report a strong association between plasma IFN-γ and CXCL-10, CXCL-9 levels. Enhanced parasite burden positively correlates with increased expression of CXCL10, CXCL9, IFN-γ and IL-10. Overall our result indicates that VL patients have an elevated inflammatory chemokine milieu which correlated with disease severity. However, expression of their chemokine receptors was significantly impaired, which may have contributed to reduced frequencies of blood monocytes and neutrophils in peripheral blood. In contrast, enhanced expression of CCR7 was associated with increased numbers of activated T cells in circulation. These findings highlight the importance of chemokines for recruitment of various cell populations in VL, and the knowledge gained may help in global understandings of the complex interaction between chemokines and pathological processes, and therefore will contribute towards the design of novel chemokine based immunological therapies against VL.     

Lymphocyte traffic control by chemokines

In contrast to the remarkable chemokine responses of phagocytes and monocytes that were documented early on, lymphocytes have been considered for a long time to be poor targets for chemokine action. This view has changed dramatically with the discovery that peripheral blood T cells need to be activated before they can migrate in response to inflammatory chemokines. These chemokines do not act on the bulk of resting T cells that are in circulation. The identification of a new group of chemokines that selects resting, as opposed to effector, T and B cells was very exciting. These inflammation-unrelated chemokines affect transendothelial migration and localization of progenitor and mature lymphocytes in lymphoid and nonlymphoid tissues. Here, we summarize the current view of chemokine-mediated lymphocyte traffic and focus on the molecular mechanisms by which T cell responses to chemokines are modulated. Recent developments in this area justify the hypothesis that the distinct migration patterns of lymphocytes throughout their life cycle--that is, during lymphopoiesis, antigen-dependent priming, inflammation and immune surveillance--are finely tuned by changing sets of chemokines that are selective for developmentally regulated chemokine receptors. Thus, the chemokine system assures that cell traffic during inflammatory responses occurs in the proper spatial and temporal fashion and disturbance of this system, therefore, can lead to inflammatory disease.     

Chemokine-induced cutaneous inflammatory cell infiltration in a model of Hu-PBMC-SCID mice grafted with human skin

Recently, certain chemokines and chemokine receptors have been preferentially associated with the selective recruitment in vitro of type 1 T cells, such as IP-10 and its receptor CXCR3, or type 2 T cells such as monocyte-derived chemokine (MDC) and eotaxin and their receptors CCR4 and CCR3. Very few models have provided confirmation of these findings in vivo. Taking advantage of the humanized SCID mouse model grafted with autologous human skin, the ability of the chemokines IP-10, MDC, eotaxin, and RANTES to stimulate cell recruitment was investigated. Intradermal IP-10 injection resulted in an influx of CD4+ T lymphocytes but also surprisingly in the recruitment of dendritic cells. MDC recruited mainly CD8+ T lymphocytes, and had little effect on eosinophils. As predicted, eotaxin was a potent inducer of eosinophil and basophil migration, also recruiting CD4+ T cells. RANTES, a ubiquitous chemokine associated with both type 1 and type 2 profiles, was able to recruit all cell types. CXCR3-positive cells were preferentially recruited by IP-10, whereas CCR3- and CCR4-positive cells were predominantly found after injection of eotaxin and MDC. Thus, in a human environment in vivo, some chemokines have the ability to recruit cells expressing chemokine receptors preferentially expressed on type 1 or type 2 cells. Further investigations revealed that MDC and eotaxin induced the recruitment of type 2, but not type 1, cytokine-producing cells. RANTES, on the other hand, induced the migration of both type 1 and type 2 cytokine-secreting cells, whereas IP-10 did not induce the recruitment of either subtype. These studies provide detailed information on the properties of MDC, eotaxin, IP-10, and RANTES as chemotactic molecules in skin in vivo. The use of the humanized SCID mouse model grafted with human skin is validated as a useful model for the evaluation of chemokine function in the inflammatory reaction, and suggests that therapeutic targeting of certain chemokines might be of interest in diseases associated preferentially with a type 1 or type 2 profile.     

T细胞相关趋化因子及受体的研究进展

T细胞在发育、成熟、活化及发挥生物学效应的各个阶段表达不同的趋化因子受体。T细胞相关趋化因子及其受体的表达在不同的细胞类群上具有时相和分布的差异,并通过趋化因子与其受体特异性结合的模式,参与T细胞的发育过程,调控细胞的定向迁移,从而影响局部甚至整个机体的免疫状态。此外,它还在炎症、感染、肿瘤、自身免疫疾病等众多病理生理的过程中发挥重要作用。在这一领域的深入研究将为相关疾病的预防和治疗提供新的思路和途径。     

Association of antigen specificity and migratory capacity of memory T cells in rheumatoid arthritis

Among the T cell pool of multiple specificities in the rheumatoid synovial tissues (ST) we have previously shown a lack of proliferative response of T cells to Acanthamoeba polyphaga [1]. In contrast, peripheral blood (PB) derived T cells proliferate to the antigen. The aim of the present study was to establish whether there is a preferential migration of some T cell specificities to the joint in rheumatoid arthritis (RA) patients dependent on the chemokine system, and to identify which chemokine receptors are involved in the migratory process. For this purpose, PB-derived T cell lines and clones from RA patients specific for A. polyphaga, herpes simplex virus (HSV) and Campylobacter jejuni were developed. Their migratory capacities towards ST-derived chemokine supernatants were analysed. Expression of CCR1, CCR2, CCR5, CCR6, CCR7, CXCR3 and CXCR4 were analysed by FACS, and attracting chemokines were identified by blocking studies. We found that the migratory capacities of T cells specific for C. jejuni and HSV were markedly higher against synovial chemokines than T cells specific for A. polyphaga. CCR5 and CXCR3 were expressed by all high-migrating T cell lines and clones. CCR2 was expressed at higher levels on the high-migrating T cell lines compared with the low-migrating A. polyphaga lines. Neutralization of RANTES (regulated upon activation normal T cell expressed and secreted) in the ST cell-derived supernatant reduced T cell migration of all T cell lines and clones by 60-90%, while neutralization of MCP-1 reduced the migratory capacity of CCR2-expressing T cells by 45-80%. In conclusion, the ability of T cells to migrate towards chemokines produced by ST cells is associated with the T cell specificity. Blocking of single chemokines substantially reduced the migratory capacity of memory T cells to ST cell-derived supernatant indicating unique roles for each chemokine receptor in the process of T cell migration.     

Chemoattractant receptors expressed on type 2 T cells and their role in disease

The existence of two functionally distinguished populations among T cells has been established in both mice and humans. Type 1 T helper (Th1) cells are involved in the defense against intracellular bacteria and many viruses, while type 2 Th cells (Th2) are the major actors in the response against parasites and play a central role in allergic inflammation. More recently, several data have suggested that some chemokine receptors are tightly regulated on T cells, and in accordance with this selective expression, Th1 and Th2 cells can be differentially recruited by specific chemokines to the inflammatory sites. Among Th2-associated chemokine receptors, CCR3, CCR4 and CCR8 have been described to play a central role in allergic inflammation. However, CCR3 is mainly expressed on basophils, eosinophils and mast cells, but it is poorly expressed by Th2 cells, and CCR4 is also expressed by Th subsets different from Th2 cells. So far, the chemoattractant receptors which among T cells appear to be selectively expressed by Th2 cells or their subsets are CCR8 and CRTH2. The ligand for CRTH2 is not a chemokine, but is prostaglandin (PG)D2, which is able to attract basophils, eosinophils, Th2 cells and type 2 cytotoxic (Tc2) CD8+ T lymphocytes. The selective expression of CRTH2 on Th2 and Tc2 cells may be useful to develop new therapeutic strategies against allergic diseases and against other immune disorders. Additional studies, however, are required to understand its effective importance in the induction and maintenance of Th2- or Tc2-mediated response and inflammation.     

Fractalkine and macrophage-derived chemokine: T cell-attracting chemokines expressed in T cell area dendritic cells.

Dendritic cells (DC) are a system of antigen-presenting cells specialized in interaction with T cells. Recently it has been reported that DC can produce CC (beta) chemokines that attract T cells. In this study we isolated mouse fractalkine and macrophage-derived chemokine (MDC) belonging to CX3C (delta) and CC chemokine families, respectively, from bone marrow-derived mature DC. While expression of fractalkine, which has so far been only examined in the brain and in vitro endothelial cells so far, was rather ubiquitous, MDC, which has been reported to be synthesized by macrophages and DC, was expressed specifically in the thymus and lymph node. This is the first report that indicates fractalkine expression by DC. Expression of fractalkine and MDC mRNA increased with maturation of DC during in vitro culture of bone marrow cells. Spleen- and epidermis-derived mature DC in culture also expressed these chemokines. Furthermore, their expression was detected selectively by Northern hybridization in CD11c+ B220- DC freshly purified from lymph nodes, and in large stellate cells in the lymph node T cell areas by in situ hybridization. Conditioned media of 293T cells transfected with these chemokine cDNA were chemotactic to Con A-activated splenic T cells as well as the mouse T cell line EL4. In conclusion, while fractalkine and MDC belong to different families of chemokines, both may be involved in recruitment of T cells for interaction with mature DC in the immune response.     

Chemokine receptor trafficking and viral replication

Summary: Chemokines and chemokine receptors have emerged as crucial factors controlling the development and function of leukocytes. Recent studies have indicated that, in addition to these essential roles, both chemokines and chemokine receptors play critical roles in viral infection and replication. Not only are chemokine receptors key components of the receptor/fusion complexes of primate immunodeficiency viruses, hut chemokines can also influence virus entry and infection. Many viruses, in particular herpesviruses, encode chemokines and chemokine receptors that influence the replication of both the parent virus and other unrelated viruses. The cell surface expression of the chemokine receptors is regulated through their interaction with membrane trafficking pathways, ligands induce receptor internalization and downmodulation through endocytosis, and recycling is regulated within endosomes. Pan of the mechanism through which chemokines protect cells from HIV infection is through ligand-induced internalization of the specific chemokine receptor co-receptors. In addition, mechanisms may exist to regulate the trafficking of newly synthesized receptors to the cell surface. Here we discuss aspects of the mechanisms through which chemokine receptors interact with membrane-trafficking pathways and the influence of these interactions on viral replication.     

Chemokines,chemokine receptors and CD4+CD25+ regulatory T cells

The fields of regulatory T (Treg) cells and chemokines/chemokine receptors have progressed rapidly in the last few years. Treg cells, especially CD4⁺CD25⁺ Treg cells, play a critical role in maintaining self-tolerance and immune homeostasis. Chemokines and chemokine receptors are crucial for lymphoid development, homing and immunological regulation. This review will discuss the biological effects of chemokines and chemokine receptors on regulating the migration and development of CD4⁺CD25⁺ Treg cells, and the potential clinical implications of these findings when considering chemokine receptors as therapeutic targets.