Human cytomegalovirus inhibits the migration of immature dendritic cells by down-regulating cell-surface CCR1 and CCR5.
Dendritic cells (DC) play a key role in the host immune response to infections. Human cytomegalovirus (HCMV) infection can inhibit the maturation of DC and impair their ability to stimulate T cell proliferation and cytotoxicity. In this study, we assessed the effects of HCMV infection on the migratory behavior of human DC. The HCMV strain TB40/E inhibited the migration of immature monocyte-derived DC in response to inflammatory chemokines by 95% 1 day after infection. This inhibition was mediated by early viral replicative events, which significantly reduced the cell-surface expression of CC chemokine receptor 1 (CCR1) and CCR5 by receptor internalization. HCMV infection also induced secretion of the inflammatory chemokines CC chemokine ligand 3 (CCL3)/macrophage inflammatory protein-1alpha (MIP-1alpha), CCL4/MIP-1beta, and CCL5/regulated on activation, normal T expressed and secreted (RANTES). Neutralizing antibodies for these chemokines reduced the effects of HCMV on chemokine receptor expression and on DC migration by approximately 60%. Interestingly, the surface expression of the lymphoid chemokine receptor CCR7 was not up-regulated after HCMV infection on immature DC, and immature-infected DC did not migrate in response to CCL19/MIP-3beta. These findings suggest that blocking the migratory ability of DC may be a potent mechanism used by HCMV to paralyze the early immune response of the host.
Varani
Stefania
S
Department of Medicine, Karolinska Systems Biomedicine Center, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Frascaroli
Giada
G
Homman-Loudiyi
Mohammed
M
Feld
Sari
S
Landini
Maria Paola
MP
Söderberg-Nauclér
Cecilia
C
D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology* / Q000502:physiology / Q000821:virology*; D015536:Down-Regulation; D006801:Humans; D054389:Receptors, CCR1; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000276:immunology*; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000276:immunology*; D014779:Virus Replication
C515300:CCR1 protein, human; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D019707:Receptors, Chemokine