Impaired lymphoid chemokine-mediated migration due to a block on the chemokine receptor switch in human cytomegalovirus-infected dendritic cells.

Section of Infection and Immunity. Department of Medicine, University of Wales College of Medicine, Cardiff, United Kingdom.
Journal of Virology (Impact Factor: 4.65). 04/2004; 78(6):3046-54. DOI: 10.1128/JVI.78.6.3046-3054.2004
Source: PubMed

ABSTRACT Dendritic cell (DC) migration from the site of infection to the site of T-cell priming is a crucial event in the generation of antiviral T-cell responses. Here we present to our knowledge the first functional evidence that human cytomegalovirus (HCMV) blocks the migration of infected monocyte-derived DCs toward lymphoid chemokines CCL19 and CCL21. DC migration is blocked by viral impairment of the chemokine receptor switch at the level of the expression of CCR7 molecules. The inhibition occurs with immediate-early-early kinetics, and viral interference with NF-kappaB signaling is likely to be at least partially responsible for the lack of CCR7 expression. DCs which migrate from the infected cultures are HCMV antigen negative, and consequently they do not stimulate HCMV-specific CD8(+) T cells, while CD4(+)-T-cell activation is not impaired. Although CD8(+) T cells can also be activated by alternative antigen presentation mechanisms, the spatial segregation of naive T cells and infected DCs seems a potent mechanism of delaying the generation of primary CD8(+)-T-cell responses and aiding early viral spread.

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    ABSTRACT: The chemokine receptor CCR7 plays a crucial role in the homing of central memory and naive T cells to peripheral lymphoid organs. Here, we show that the HIV-1 accessory protein Vpu downregulates CCR7 on the surface of CD4(+) T cells. Vpu and CCR7 were found to specifically interact and colocalize within the trans-Golgi network, where CCR7 is retained. Downmodulation of CCR7 did not involve degradation or endocytosis and was strictly dependent on Vpu expression. Stimulation of HIV-1-infected primary CD4(+) T cells with the CCR7 ligand CCL19 resulted in reduced mobilization of Ca(2+), reduced phosphorylation of Erk1/2, and impaired migration toward CCL19. Specific amino acid residues within the transmembrane domain of Vpu that were previously shown to be critical for BST-2 downmodulation (A14, A18, and W22) were also necessary for CCR7 downregulation. These results suggest that BST-2 and CCR7 may be downregulated via similar mechanisms.
    Cell reports. 06/2014;
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    ABSTRACT: Primary infection of healthy individuals with human cytomegalovirus (HCMV) is normally asymptomatic but results in the establishment of a lifelong infection of the host. One important cellular reservoir of HCMV latency is the CD34+ haematopoietic progenitor cells resident in the bone marrow. Viral gene expression is highly restricted in these cells with an absence of viral progeny production. However, cellular differentiation into mature myeloid cells is concomitant with the induction of a full lytic transcription program, DNA replication and, ultimately, the production of infectious viral progeny. Such reactivation of HCMV is a major cause of morbidity and mortality in a number of immune-suppressed patient populations. Our current understanding of HCMV carriage and reactivation is that cellular differentiation of the CD34+ progenitor cells through the myeloid lineage, resulting in terminal differentiation to either a macrophage or dendritic cell (DC) phenotype, is crucial for the reactivation event. In this mini-review, we focus on the interaction of HCMV with DCs, with a particular emphasis on their role in reactivation, and discuss how the critical regulation of viral major immediate-early gene expression appears to be delicately entwined with the activation of cellular pathways in differentiating DCs. Furthermore, we also explore the possible immune consequences associated with reactivation in a professional antigen presenting cell and potential countermeasures HCMV employs to abrogate these.
    Frontiers in Microbiology 08/2014; 5:389. · 3.94 Impact Factor
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    ABSTRACT: Background Dendritic cells (DCs) are professional antigen-presenting cells with vital roles in the activation of host immunity. Ticks are bloodsucking arthropods that secrete bioactive compounds with immunomodulatory properties via their saliva. It is known that some tick species modulate the biology of DCs with different intensities; however, studies on Amblyomma cajennense, the Cayenne tick, have not yet been performed, although this species is considered one of the most capable of modulating immune responses of different hosts.Methods Engorged female ticks were stimulated with dopamine to induce salivation, and saliva was pooled. The effects of tick saliva on the biology of dendritic cells were assessed by examining DC differentiation, maturation, migration, cellular viability, cytokine production and expression of surface markers by flow cytometry and ELISA. Competitive enzyme immunoassays (EIA) were used to measure saliva prostaglandin-E2 (PGE2). Statistical significance was determined by ANOVA followed by Tukey¿s post-test or by the Kruskal-Wallis test with the Dunns post-test.ResultsIn this work, we demonstrated that the presence of A. cajennense saliva to bone marrow cultures inhibit DC differentiation. This inhibition was not accompanied by inhibition or induction of stimulatory and co-stimulatory molecules such as MHC-II, CD40, CD80 or CD86. Immature and mature DCs that were pre-exposed to saliva showed reduced migration toward the chemokines RANTES and MIP-3ß. This inhibition was associated to a reduced expression of CCR5 (the receptor for RANTES) or CCR7 (the receptor for MIP-3ß) induced by the presence of saliva in the cultures. Tick saliva also inhibited IL-12p40, IL-6 and TNF-¿ in a concentration-dependent manner while potentiating IL-10 cytokine production by DCs stimulated with Toll-like receptor-4 ligand. Additionally, A. cajennense tick saliva inhibited the expression of CD40 and CD86 in mature DCs while potentiating the expression of PD-L1. PGE2 was detected as one of the constituents of saliva at a concentration of¿~¿80 ng/ml, and we believe that most of the results reported herein are due to the presence of PGE2.Conclusions These results help to understand the tick-host interaction and demonstrate that A. cajennense ticks appear to have mechanisms for modulating host immune cells, including DCs.
    Parasites & Vectors 01/2015; 8(1):22. · 3.25 Impact Factor

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