Shaping phenotype, function, and survival of dendritic cells by cytomegalovirus-encoded IL-10.
Human dendritic cells (DCs) are essential for the antiviral immune response and represent a strategically important target for immune evasion of viruses, including human CMV (HCMV). Recently, HCMV has been discovered to encode a unique IL-10 homologue (cmvIL-10). In this study we investigated the capacity of cmvIL-10 to shape phenotype, function, and survival of DCs. For comparison we included human IL-10 and another IL-10 homologue encoded by EBV, which does not directly target DCs. Interestingly, cmvIL-10 strongly activated STAT3 in immature DCs despite its low sequence identity with human IL-10. For most molecules cmvIL-10 blocked LPS-induced surface up-regulation, confirming its role as an inhibitor of maturation. However, a small number of molecules on LPS-treated DCs including IDO, a proposed tolerogenic molecule, showed a different behavior and were up-regulated in response to cmvIL-10. Intriguingly, the expression of C-type lectin DC-specific ICAM-grabbing nonintegrin, a receptor for HCMV infection found exclusively on DCs, was also enhanced by cmvIL-10. This phenotypic change was mirrored by the efficiency of HCMV infection. Moreover, DCs stimulated with LPS and simultaneously treated with cmvIL-10 retained the function of immature DCs. Finally, cmvIL-10 increased apoptosis associated with DC maturation by blocking up-regulation of the antiapoptotic long form cellular FLIP. Taken together, these findings show potential mechanisms by which cmvIL-10 could assist HCMV to infect DCs and to impair DC function and survival.
Institute of Virology, Charité Medical School, Berlin, Germany.
Martin J
MJ
Raftery
Dörte
D
Wieland
Stefanie
S
Gronewald
Annette A
AA
Kraus
Thomas
T
Giese
Günther
G
Schönrich
D017209:Apoptosis / Q000276:immunology / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003587:Cytomegalovirus / Q000235:genetics / Q000378:metabolism*; D003586:Cytomegalovirus Infections / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D037181:Lectins, C-Type / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D016753:Interleukin-10; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C494086:STAT3 protein, human