Paracrine inhibition of GM-CSF signaling by human cytomegalovirus in monocytes differentiating to dendritic cells.
A primary HCMV infection or virus reactivation may cause severe disease in hosts with a deficient immune system. The virus can disturb both innate and adaptive immunity by targeting dendritic cell (DC) functions. Monocytes, the precursors of DCs in vivo (MoDCs), are the primary targets of HCMV; they can also harbor latent virus. The DCs generated from infected monocytes (CMV-MoDCs) have an altered phenotype and functional defects. We have shown that CMV-MoDCs do not secrete IL-12 in response to lipopolysaccharide stimulation, cannot ingest dead cells, induce T(H)1 differentiation, or the proliferation of naive allogeneic CD4(+) T cells. We found that the GM-CSF signaling in an entire population of CMV-MoDCs was impaired, although only half of the cells were productively infected, and that IL-6 secretion and suppressors of cytokine signaling 3 induction contributed to this bystander effect. We also showed that MoDCs derived ex vivo from monocytes of viremic patients had the same altered phenotype as CMV-MoDCs, including decreased STAT5 phosphorylation, indicating defective GM-CSF signaling. We have thus described a new mechanism of HCMV-induced immunosupression, indicated how infection may disturb both GM-CSF-dependent physiologic processes and proposed GM-CSF-based therapeutic approaches.
Inserm U, Toulouse, France.
Jérome
J
Carlier
Hélène
H
Martin
Bernard
B
Mariamé
Benjamin
B
Rauwel
Catherine
C
Mengelle
Hugo
H
Weclawiak
Alain
A
Coaquette
Charline
C
Vauchy
Pierre
P
Rohrlich
Nassim
N
Kamar
Lionel
L
Rostaing
Georges
G
Herbein
Christian
C
Davrinche
D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000276:immunology* / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D019899:Paracrine Communication / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000276:immunology / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
D018793:Interleukin-13; D015850:Interleukin-6; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; C106644:SOCS3 protein, human; D050799:STAT5 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor