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: 4.44). 04/2004; 78(6):3046-54. DOI: 10.1128/JVI.78.6.3046-3054.2004
Source: PubMed


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-κB 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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Available from: Zsuzsanna Tabi
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    • "What became clear from such data was that HCMV infection of DCs resulted in a severe down-regulation of cell surface molecules which impacted on the normal function of DCs as APCs (Riegler et al., 2000; Grigoleit et al., 2002; Moutaftsi et al., 2002, 2004; Hertel et al., 2003; Lee et al., 2006, 2011; Huang et al., 2012). Although viral genes encoding immune evasion functions are expressed in all cell types, the sheer abundance of immune-evasins expressed by the virus suggests the evolution of an intimate relationship between HCMV and key immune effector cells – e.g., the DC lineage. "
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    • "A switch from CCR5 to CCR7 during DC maturation enables the cells respond to these chemokines. However, HCMV can prevent this chemokine receptor switch in infected moDCs—and thereby inhibit migration of mature moDCs in response to CCL19 and CCL21.70 In immature moDCs, HCMV infection impairs chemotaxis in response to CCL3 and CCL5, and internalizes CCR1 and CCR5, but does not affect CCR7.71 "
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    • "Further, HCMV-infected, immature Mo- DCs have fewer surface HLA class I and class II molecules and impaired migratory and immunostimulatory capacity [74] [81] [82]. The virus also inhibits Mo-DC maturation and impedes the migration of mature DCs in response to lymphoid stimuli and induction of T-cell proliferation [75] [82] [83]. Similarly, on infection with HCMV, activation markers are downregulated in mature Langerhans DCs, decreasing their ability to stimulate T-cell proliferation [84] [85]. "
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