Anatomic localization of immature and mature dendritic cell subsets in dermatomyositis and polymyositis: Interaction with chemokines and Th1 cytokine-producing cells

OBJECTIVE: To clarify the involvement of dendritic cells (DCs), chemokines, and proinflammatory Th1 cytokines in the pathogenesis of the chronic muscle diseases dermatomyositis (DM) and polymyositis (PM). METHODS: We characterized by immunohistochemistry the DC subsets and their interaction with cells producing chemokines and the Th1 cytokines interleukin-17 (IL-17) and interferon-gamma (IFNgamma). Immature and mature DCs were defined by the expression of CD1a and DC-LAMP/CD83, respectively. RESULTS: Immature DCs were mainly detected in lymphocytic infiltrates in DM and PM muscle tissue samples. Mature DCs were detected in perivascular infiltrates and surrounded muscle fibers. IL-17-positive and IFNgamma-positive cells were also observed in perivascular infiltrates in both cases. We then focused on the expression of the CCL20/CCR6 chemokine/receptor complex, which controls immature DC migration, and on the expression of the CCL19/CCR7 and CCL21/CCR7 chemokine/receptor complexes, which control mature DC migration. CCL20 and CCR6 colocalized in lymphocytic infiltrates in DM and PM samples. CCL21 was rarely observed in DM samples and never observed in PM samples. CCL19- and CCR7-expressing cells were absent in both tissues. CONCLUSION: The close association between CCL20/CCR6 and immature DCs suggests the contribution of CCL20 to CCR6+ immature DC homing. Detection of mature DCs in DM and PM muscle tissue samples despite the lack of CCL19 and CCR7 is evidence for a local maturation of DCs in inflammatory muscle tissue without lymphoid organ organization.     

Dendritic cell chemotaxis in 3D under defined chemokine gradients reveals differential response to ligands CCL21 and CCL19

Dendritic cell (DC) homing to the lymphatics and positioning within the lymph node is important for adaptive immunity, and is regulated by gradients of CCL19 and CCL21, ligands for CCR7. Despite the importance of DC chemotaxis, it is not well understood how DCs interpret gradients of these chemokines in a complex 3D microenvironment. Here, we use a microfluidic device that allows rapid establishment of stable gradients in 3D matrices to show that DC chemotaxis in 3D can respond to CCR7 ligand gradients as small as 0.4%, which helps explain how DCs sense lymphatic vessels in an environment where broadcast distance for chemokine diffusion is hindered by convective flows into the vessel. Interestingly, DCs displayed similar sensitivities to both chemokines at small gradients (≤ 60 nM/mm), but migrated more efficiently towards higher gradients of CCL21, which unlike CCL19 binds strongly to matrix proteoglycans and signals without the need for internalization. Furthermore, cells preferentially migrated towards CCL21 when exposed to equal and opposite gradients of CCL21 and CCL19 simultaneously, even when matrix-binding of CCL21 was prevented. Although these ligands have similar binding affinity to CCR7, our results demonstrate that, in a 3D environment, CCL21 is a more potent directional cue for DC migration than CCL19. These findings provide new quantitative insight into DC chemotaxis in a physiological 3D environment and suggest how CCL19 and CCL21 may signal differently to fine-tune DC homing and positioning within the lymphatic system. These results also have broad relevance to other systems of cell chemotaxis, which remain poorly understood in the 3D context.     

Anatomic localization of immature and mature dendritic cell subsets in dermatomyositis and polymyositis: Interaction with chemokines and Th1 cytokine–producing cells

Objective

To clarify the involvement of dendritic cells (DCs), chemokines, and proinflammatory Th1 cytokines in the pathogenesis of the chronic muscle diseases dermatomyositis (DM) and polymyositis (PM).

Methods

We characterized by immunohistochemistry the DC subsets and their interaction with cells producing chemokines and the Th1 cytokines interleukin‐17 (IL‐17) and interferon‐γ (IFNγ). Immature and mature DCs were defined by the expression of CD1a and DC‐LAMP/CD83, respectively.

Results

Immature DCs were mainly detected in lymphocytic infiltrates in DM and PM muscle tissue samples. Mature DCs were detected in perivascular infiltrates and surrounded muscle fibers. IL‐17–positive and IFNγ‐positive cells were also observed in perivascular infiltrates in both cases. We then focused on the expression of the CCL20/CCR6 chemokine/receptor complex, which controls immature DC migration, and on the expression of the CCL19/CCR7 and CCL21/CCR7 chemokine/receptor complexes, which control mature DC migration. CCL20 and CCR6 colocalized in lymphocytic infiltrates in DM and PM samples. CCL21 was rarely observed in DM samples and never observed in PM samples. CCL19‐ and CCR7‐expressing cells were absent in both tissues.

Conclusion

The close association between CCL20/CCR6 and immature DCs suggests the contribution of CCL20 to CCR6+ immature DC homing. Detection of mature DCs in DM and PM muscle tissue samples despite the lack of CCL19 and CCR7 is evidence for a local maturation of DCs in inflammatory muscle tissue without lymphoid organ organization.

     

The chemokine CCL21 modulates lymphocyte recruitment and fibrosis in chronic hepatitis C

BACKGROUND AND AIMS: The chemokines CCL19 and CCL21 bind CCR7, which is involved in the organization of secondary lymphoid tissue and is expressed during chronic tissue inflammation. We investigated the expression of CCL21 and CCR7 in chronic hepatitis C. The effects of CCL21 on hepatic stellate cells (HSCs) were also studied. METHODS: Expression of CCL21 was assessed by in situ hybridization and immunohistochemistry. CCR7 on T cells was analyzed by flow cytometry. Cultured human HSCs were studied in their activated phenotype. RESULTS: In patients with chronic hepatitis C, expression of CCL21 and CCR7 was up-regulated. CCL21 was detected in the portal tracts and around inflammatory lymphoid follicles, in proximity to T lymphocytes and dendritic cells, which contributed to expression of this chemokine. Expression of CCR7 was also increased in patients with primary biliary cirrhosis. Intrahepatic CD8(+) T lymphocytes isolated from patients with chronic hepatitis C had a significantly higher percentage of positivity for CCR7 than those from healthy controls, and the expression of CCR7 was associated with that of CXCR3. Cultured HSCs expressed functional CCR7, the activation of which stimulated cell migration and accelerated wound healing in an in vitro model. Exposure of HSCs to CCL21 triggered several signaling pathways, including extracellular signal-regulated kinase, Akt, and nuclear factor kappaB, resulting in induction of proinflammatory genes. CONCLUSIONS: Expression of CCL21 during chronic hepatitis C is implicated in the recruitment of T lymphocytes and the organization of inflammatory lymphoid tissue and may promote fibrogenesis in the inflamed areas via activation of CCR7 on HSCs.     

Simian immunodeficiency virus dramatically alters expression of homeostatic chemokines and dendritic cell markers during infection in vivo

Dendritic cells (DCs) are potent antigen-presenting cells that likely play multiple roles in human immunodeficiency virus type 1 (HIV-1) pathogenesis. We used the simian immunodeficiency virus (SIV)/macaque model to study the effects of infection on homeostatic chemokine expression and DC localization directly in secondary lymphoid tissues. SIV infection altered the expression of chemokines (CCL19/MIP-3beta, CCL21/ 6Ckine, and CCL20/MIP-3alpha) and of chemokine receptors (CCR7 and CCR6) that drive DC trafficking. CCL19/MIP-3beta, CCL20/MIP-3alpha, CCR6, and CCR7 expression increased in lymph nodes during the early systemic burst of viral replication (acute infection), whereas CCL21/6Ckine expression progressively decreased throughout disease to AIDS. Parallel with the SIV-induced perturbations in chemokine expression were changes in the expression of the DC-associated markers, DC-SIGN, DC-LAMP, and DECTIN-1. During AIDS, DC-LAMP mRNA expression levels were significantly reduced in lymph nodes and spleen, and DC-SIGN levels were significantly reduced in spleen. These findings suggest that the disruption of homeostatic chemokine expression is responsible, in part, for alterations in the networks of antigen-presenting cells in lymphoid tissues, ultimately contributing to systemic immunodeficiency.     

CCR7 ligands induce rapid endocytosis in mature dendritic cells with concomitant up-regulation of Cdc42 and Rac activities

Although chemokines are well known to function in chemotaxis, additional roles for these molecules in the immune system are not well understood. Dendritic cells (DCs) developmentally regulate the expression of chemokine receptors to facilitate their migration from the peripheral tissues to regional lymph nodes. Expressions of CCR1 and CCR5 on immature DCs are down-regulated on maturation, whereas CCR7 is selectively expressed on mature DCs. In the present study, we examined the effects of CCL19 and CCL21, 2 CCR7 ligands, on endocytosis of fluorescein isothiocyanate (FITC)-dextran by murine DCs. Both CCL19 and CCL21 markedly induced rapid uptake of FITC-dextran by mature DCs but not immature DCs. In contrast, CCL3, a ligand of CCR1 and CCR5, induced rapid uptake of FITC-dextran by immature DCs but not mature DCs. CCL19-induced endocytosis could be completely blocked by Clostridium difficile toxin B, which inhibits the Rho guanosine triphosphatase proteins, Rho, Rac, and Cdc42. This process was not abrogated by Y-27632, a specific inhibitor of Rho-associated kinase. In addition, CCL19 rapidly enhanced Cdc42 and Rac activity in mature DCs. These findings demonstrate that certain chemokines induce rapid endocytosis in each relevant DC population. It is suggested that CCR7 ligands activate Cdc42 and Rac, thereby inducing the endocytosis in mature DCs.     

Prostaglandin E2 is a key factor for CCR7 surface expression and migration of monocyte-derived dendritic cells

Dendritic cells (DCs) are potent antigen-presenting cells that are able to initiate and modulate immune responses and are hence exploited as cellular vaccines for immunotherapy. Their capacity to migrate from peripheral tissues to the T-cell areas of draining lymph nodes is crucial for the priming of T lymphocytes. In this study, we investigated how the maturation of human monocyte-derived DCs (MoDCs) by several different stimuli under serum-free conditions affected their T-cell stimulatory function, cytokine secretion, and migratory behavior. Surprisingly, we found that for all maturation stimuli tested, the addition of prostaglandin E2 (PGE2) was required for effective migration of MoDCs toward the lymph node-derived chemokines CCL19 (EBI1 ligand chemokine/macrophage inflammatory protein--3beta) and CCL21 (secondary lymphoid tissue chemokine [SLC]/6Ckine). Costimulation with PGE2 enhanced the expression of the CCL19/CCL21 receptor CCR7 on the cell surface of MoDCs when they were matured with soluble CD40 ligand or proinflammatory cytokines, but did not affect CCR7 expression of polyI:C-stimulated MoDCs. The effects of PGE2 on MoDCs were mediated through increased cyclic adenosine monophosphate by 2 of the known PGE2 receptors, EP2 and EP4, which are expressed and down-regulated after PGE2 binding in these cells. In conclusion, our results suggest that signals provided by the proinflammatory mediator PGE2 are crucial for MoDCs to acquire potent T-helper cell stimulatory capacity and substantial chemotactic responsiveness to lymph node-derived chemokines. This is a new and important parameter for the preparation of MoDCs as cellular vaccines in tumor immunotherapy. (Blood. 2002;100:1354-1361)     

CCL19/CCL21-triggered signal transduction and migration of dendritic cells requires prostaglandin E2

The control of dendritic cell (DC) migration is pivotal for the initiation of cellular immune responses. When activated with inflammatory stimuli, the chemokine receptor CCR7 is up-regulated on DCs. Activated DCs home to lymphoid organs, where the CCR7 ligands CCL19 and CCL21 are expressed. We previously found that human monocyte-derived DCs (MoDCs) exclusively migrated to CCL19 and CCL21 when matured in the presence of prostaglandin (PG) E2. Because PGE2 did not alter CCR7 cell surface expression, we examined whether PGE2 may exert its effect by coupling CCR7 to signal transduction modules. Indeed, stimulation with CCR7 ligands led to enhanced phosphatidylinositol-3-kinase-mediated phosphorylation of protein kinase B when MoDCs were matured in the presence of PGE2. Moreover, CCL19/CCL21-induced intracellular calcium mobilization in MoDCs occurred only when PGE2 was present during maturation. MoDC migration to CCL19 and CCL21 was dependent on phospholipase C and intracellular calcium flux but not on phosphatidylinositol-3 kinase. Hence, our data provide insight into CCL19/CCL21-triggered signal transduction pathways and identify a novel function for PGE2 in controlling the migration of mature MoDCs by facilitating CCR7 signal transduction.     

Chemokine receptor CCR7 induces intracellular signaling that inhibits apoptosis of mature dendritic cells

Acquisition of CCR7 expression is an important phenotype change during dendritic cell (DC) maturation that endows these cells with the capability to migrate to lymph nodes. We have analyzed the possible role of CCR7 on the regulation of the survival of DCs. Stimulation with CCR7 ligands CCL19 and CCL21 inhibits apoptotic hallmarks of serum-deprived DCs, including membrane phosphatidylserine exposure, loss of mitochondria membrane potential, increased membrane blebs, and nuclear changes. Both chemokines induced a rapid activation of phosphatidylinositol 3'-kinase/Akt1 (PI3K/Akt1), with a prolonged and persistent activation of Akt1. Interference with PI3K, Gi, or G protein betagamma subunits abrogated the effects of the chemokines on Akt1 activation and on survival. In contrast, inhibition of extracellular signal-related kinase 1/2 (Erk1/2), p38, or c-Jun N-terminal kinase (JNK) was ineffective. Nuclear factor-kappaB (NFkappaB) was involved in the antiapoptotic effects of chemokines because inhibition of NFkappaB blunted the effects of CCL19 and CCL21 on survival. Furthermore, chemokines induced down-regulation of the NFkappaB inhibitor IkappaB, an increase of NFkappaB DNA-binding capability, and translocation of the NFkappaB subunit p65 to the nucleus. In summary, in addition to its well-established role in chemotaxis, we show that CCR7 also induces antiapoptotic signaling in mature DCs.     

Developmental stage-specific shift in responsiveness to chemokines during human B-cell development

OBJECTIVES: To better understand the role of chemokines during human B-cell development in bone marrow. METHODS: Differentiation stage-specific B cells (pro-B, pre-B, immature, and mature) were analyzed for chemokine receptor expression and for migration to corresponding ligands. We also hypothesized that inflammatory conditions may cause the upregulation of certain chemokine receptors on early B cells, rendering them sensitive to extramedullary chemotactic cues. To test this hypothesis, we used human pre-B 697 cells to investigate whether various inflammatory agents could modify chemokine receptor expression and function. RESULTS: Chemotaxis to CXCL12 was observed for all B cell subsets. However, chemotactic responses to CCL19, CCL21, CXCL13, and CCL20 were limited to late-stage, IgM+ bone marrow B cells (immature B and mature B). Chemotactic responses to corresponding ligands correlated with the pattern of chemokine receptor expression. The expression of CCR7, however, was low on early (pro-B and pre-B) B cells and did not induce chemotaxis. Interestingly, both CCL19 and CCL21 could trigger ERK1/2 phosphorylation in early B cells. Exposure of pre-B 697 cells to TNF-alpha upregulated CCR7 and CXCR5 expression, whereas it had no effect on CCR6 surface expression. Correspondingly, TNF-alpha-stimulated pre-B cells chemotaxed towards CCL19 and CXCL13, in contrast to non-TNF-alpha-stimulated controls. CONCLUSION: We postulate that CXCR5, CCR7, and CCR6 participate in bone marrow trafficking and/or bone marrow egress of late-stage B cells under steady-state conditions, whereas inflammation-induced expression of CCR7 and CXCR5 may facilitate early B-cell emigration out of the bone marrow and their positioning in secondary lymphoid organs.     

The chemokine receptor CCR7 and alpha4 integrin are important for migration of chronic lymphocytic leukemia cells into lymph nodes

Malignant lymphocyte migration into lymph nodes is an important aspect of chronic lymphocytic leukemia (CLL), yet little is known about the processes involved. Here we demonstrate that CLL cells migrate across vascular endothelium in response to at least 3 chemokines, namely, CCL21, CCL19, and CXCL12. Moreover, transendothelial cell migration (TEM) in response to CCL21 and CCL19 was significantly higher for the malignant B cells of patients who had clinical lymph node involvement as compared with those of patients lacking such organomegaly. Furthermore, the expression of CCR7, the receptor for both CCL21 and CCL19, correlated with clinical lymphadenopathy, and blocking of CCR7 inhibited CLL cell TEM. By using immunohistochemistry we demonstrated that CCL21 and CCL19, but not CXCL12, are located in high endothelial venules and are, therefore, in an appropriate location to induce TEM. Regarding the adhesion receptors involved in TEM, alpha4 (most likely in association with beta1) and alphaLbeta2 were shown to be important in CLL cell TEM in vitro, but only the level of alpha4 expression correlated with the presence of clinical lymphadenopathy. The present studies are the first to shed light on the factors determining CLL cell entry into nodes and define the phenotype of circulating malignant cells likely to determine the pattern of lymph node enlargement in the disease.     

Disparate lymphoid chemokine expression in mice and men: no evidence of CCL21 synthesis by human high endothelial venules

T-cell homing to secondary lymphoid tissues generally depends on chemokine-induced firm adhesion in high endothelial venules (HEVs) and is primarily mediated through the CC chemokine receptor 7 (CCR7) on lymphocytes. The CCR7 ligand designated CCL21 is considered the most important trigger because it appears constitutively expressed by murine HEVs. Surprisingly, when we analyzed human tissues, no CCL21 mRNA could be detected in HEVs. In fact, CCL21 mRNA was only expressed in extravascular T-zone cells and lymphatics, whereas immunostaining revealed CCL21 protein within HEVs. This suggests that T-cell recruitment to human lymphoid tissues depends on the transcytosis of lymphoid chemokines through HEV cells because there is at present no evidence of alternative chemokine production in these cells that could explain the attraction of naive T lymphocytes.     

CCR6/CCR10-mediated plasmacytoid dendritic cell recruitment to inflamed epithelia after instruction in lymphoid tissues

Absent in peripheral tissues during homeostasis, human plasmacytoid dendritic cells (pDCs) are described in inflamed skin or mucosa. Here, we report that, unlike blood pDCs, a subset of tonsil pDCs express functional CCR6 and CCR10, and their respective ligands CCL20 and CCL27are detected in inflamed epithelia contacting blood dendritic cell antigen 2(+) pDCs. Moreover, pDCs are recruited to imiquimod-treated skin tumors in WT but not CCR6-deficient mice, and competitive adoptive transfers reveal that CCR6-deficient pDCs are impaired in homing to inflamed skin tumors after intravenous transfer. On IL-3 culture, CCR6 and CCR10 expression is induced on human blood pDCs that become responsive to CCL20 and CCL27/CCL28, respectively. Interestingly, unlike myeloid DC, blood pDCs initially up-regulate CCR7 expression and CCL19 responsiveness on IL-3 ± CpG-B and then acquire functional CCR6 and CCR10. Finally, IL-3-differentiated CCR6(+) CCR10(+) pDCs secrete high levels of IFN-α in response to virus. Overall, we propose an unexpected pDCs migratory model that may best apply for mucosal-associated lymphoid tissues. After CCR7-mediated extravasation into lymphoid tissues draining inflamed epithelia, blood pDCs may be instructed to up-regulate CCR6 and/or CCR10 allowing their homing into inflamed epithelia (in mucosae or skin). At this site, pDCs can then produce IFN-α contributing to pathogen clearance and/or local inflammation.     

Influence of ERK activation on decreased chemotaxis of mature human cord blood monocyte-derived dendritic cells to CCL19 and CXCL12

Dendritic cells (DCs) are important regulators in graft-versus-host disease (GVHD). To gain insight into cord blood (CB) DC immunology, we compared chemotactic responses of mature monocyte-derived DCs and maturation agent lipopolysaccharide (LPS)-induced signaling between CB and adult blood (AB). Mature CB DCs expressed reduced CCR7, but increased CXCR4. This was associated with reduced migratory efficiency toward both CCR7 ligand CCL19 and CXCR4 ligand CXCL12. LPS induced higher extracellular signal-regulated kinase (ERK) phosphorylation in CB than in AB DCs. Specific inhibition of ERK during CB DC maturation enhanced LPS-induced up-regulation of CCR7 and CXCR4 on CB DCs and their chemotaxis toward CCL19 and CXCL12, to a level similar to that of mature AB DCs. Overall, monocyte-derived CB DCs responded to LPS with stronger and sustained ERK activation, which negatively correlated with LPS-induced up-regulation of CCR7 and CXCR4 on CB DCs and their migratory responses. These findings may have potential relevance to better understanding DC function in CB transplantation.     

Mycobacterium tuberculosis triggers formation of lymphoid structure in murine lungs

The hallmark of pulmonary tuberculosis is the granuloma, which consists predominantly of lymphocytes and macrophages and promotes immune-cell interaction with the causative pathogen, Mycobacterium tuberculosis. Granuloma formation is a highly organized process, which depends on leukocyte recruitment facilitated by adhesion molecules and chemokines. Thus, during chronic experimental tuberculosis, granulomata display characteristics of lymphoid structures comprising follicular aggregation of B cells, formation of high endothelial venules, presence of follicular dendritic cells, and expression of the homeostatic chemokines CXCL13 and CCL19. CCR7-/- mice, which are deficient in CCL19 and CCL21 signaling, exhibit increased local inflammatory infiltrates but no follicular B-cell aggregation within those lymphoid structures. However, CCR7-deficient mice are fully capable to control pulmonary tuberculosis; at time points later than 6 weeks postinfection, they carry a lower bacterial load in peripheral organs. Our results show that, during chronic pulmonary tuberculosis in mice, the homeostatic chemokine signaling-network contributes to spatial organization of the granulomatous response, which participates in both containment of M. tuberculosis and the latter's dissemination to other organs.     

Immunohistochemical evidence of a cytokine and chemokine network in three patients with Erdheim-Chester disease: implications for pathogenesis

OBJECTIVE: Erdheim-Chester disease (ECD) is a rare form of non-Langerhans' cell histiocytosis (LCH) of unknown etiology, characterized by diffuse histiocyte infiltration of bones and soft tissue. The purpose of this study was to assess cell proliferation and expression of cytokines, chemokines, and chemokine receptors that may potentially be important in histiocyte accumulation in ECD lesions. METHODS: Biopsies were performed on 3 patients with ECD. The diagnosis of the disease was based on clinical signs including typical radiologic osteosclerosis, and on the detection of foamy CD68+,CD1a- non-Langerhans' cell histiocytes on histologic examination. The expression of the proliferation marker Ki-67 as well as of selected chemokine/chemokine receptor pairs and cytokines was analyzed by immunohistochemistry. RESULTS: In all samples, Ki-67 was undetectable in CD68+ histiocytes. Conversely, these cells expressed the chemokines CCL2 (monocyte chemotactic protein 1), CCL4/macrophage inflammatory protein 1beta (MIP-1beta), CCL5/RANTES, CCL20/MIP-3alpha, and CCL19/MIP-3beta, and their counter-receptors CCR1, CCR2, CCR3, CCR5, CCR6, and CCR7. Moreover, ECD histiocytes expressed interferon-gamma-inducible 10-kd protein (CXCL10), which is specifically induced by interferon-gamma, and interleukin-6 and RANKL, which are both implicated in bone remodeling. Finally, all cases showed a Th1-type lymphocyte infiltrate. CONCLUSION: Our data indicate that, similar to LCH, ECD lesions are characterized by a complex cytokine and chemokine network, which may orchestrate histiocyte activation and accumulation through an autocrine loop and contribute to the pathogenesis of the disease.     

Increased expression of CCL18, CCL19, and CCL17 by dendritic cells from patients with rheumatoid arthritis, and regulation by Fc gamma receptors

BACKGROUND: Dendritic cells (DC) have a role in the regulation of immunity and tolerance, attracting inflammatory cells by the production of various chemokines (CK). Fc gamma receptors (Fc gamma R) may be involved in regulation of the DC function. OBJECTIVE: To assess the expression of CK by immature (iDC) and mature DC (mDC) and its regulation by Fc gamma R in patients with RA and healthy donors (HC). METHODS: Expression of CK by DC from patients with RA and from HC was determined by real time quantitative PCR and ELISA. DC were derived from monocytes following standardised protocols. To study the potential regulation by Fc gamma R, iDC were stimulated with immune complexes (IC) during lipopolysaccharide (LPS) induced maturation. The presence of CK was studied in synovial tissue from patients with RA, osteoarthritis, and healthy subjects by RT-PCR and immunohistochemistry. RESULTS: iDC from patients with RA had markedly increased mRNA levels of the CK CCL18 and CXCL8. Upon maturation with LPS, expression of CCL18, CCL19, CXCL8, CCL3, and CCL17 increased dramatically, reaching significantly higher levels in patients with RA. Monocytes failed to express these CK, except for CXCL8 and CCL3. IC-mediated triggering of the Fc gamma R on DC from patients with highly active RA down regulated all CK, whereas the reverse was seen when DC from patients with low disease activity and healthy donors were stimulated. CCL18 was significantly increased in RA synovial tissue. CONCLUSION: Increased CK expression by DC was found in patients with RA. This expression is partly regulated by Fc gamma R triggering and results in an inhibitory DC subtype in RA upon Fc gamma R-mediated triggering.     

CCR7 ligands CCL19 and CCL21 increase permissiveness of resting memory CD4+ T cells to HIV-1 infection: a novel model of HIV-1 latency

Latent HIV-1 infection of resting memory CD4(+) T cells represents the major barrier to HIV-1 eradication. To determine whether the CCR7 ligands involved in lymphocyte migration can alter HIV-1 infection of resting CD4(+) T cells, we infected purified resting CD4(+) T cells after incubation with the chemokines CCL19 and CCL21. Incubation with CCL19 or CCL21 did not alter markers of T-cell activation or proliferation. However, after HIV-1 infection of CCL19- or CCL21-treated CD4(+) T-cells, we observed low-level HIV-1 production but high concentrations of integrated HIV-1 DNA, approaching that seen in mitogen-stimulated T-cell blasts. Restimulation of CCL19-treated infected CD4(+) T cells resulted in virus production consistent with establishment of postintegration latency. CCR7 ligands facilitate efficient entry of HIV-1 into resting CD4(+) T cells. These studies demonstrate a unique action of the chemokines CCL19 and CCL21 and provide a novel model with which to study HIV-1 latency in vitro.