Induction of CD83+CD14+ nondendritic antigen-presenting cells by exposure of monocytes to IFN-alpha.
IFN-alpha is a well-known agent for treatment of viral and malignant diseases. It has several modes of actions, including direct influence on the immune system. We investigated IFN-alpha effects on PBMC in terms of dendritic cell (DC) differentiation, as PBMC are exposed to high IFN-alpha levels during treatment of infections and cancers. We show that in vitro IFN-alpha exposure induced rapid and strong up-regulation of the DC-maturation markers CD80, CD86, and CD83 in bulk PBMC. Consistently, IFN-alpha induced up-regulation of these molecules on purified monocytes within 24 h. Up-regulation of CD80 and CD83 expression was IFN-alpha concentration-dependent. In contrast to GM-CSF + IL-4-generated DCs, most of the IFN-alpha-challenged CD83(+) cells coexpressed the monocyte marker CD14. Despite a typical mature DC immunophenotype, IFN-alpha-treated monocytes conserved phagocytic activity and never acquired a dendritic morphology. In mixed lymphocyte reactions IFN-alpha-treated monocytes were less potent than GM-CSF + IL-4-generated DCs but significantly more potent than untreated monocytes to induce T cell proliferation in bulk PBMC. However, only GM-CSF + IL-4-generated DCs were able to induce a significant proliferation of naive CD4(+) T cells. Notably, autologous memory CD4(+) T cells proliferated when exposed to tetanus toxoid-pulsed IFN-alpha-treated monocytes. At variance with untreated or GM-CSF + IL-4-exposed monocytes, those challenged with IFN-alpha showed long-lasting STAT-1 phosphorylation. Remarkably, CD83(+)CD14(+) cells were present in varicella skin lesions in close contact with IFN-alpha-producing cells. The present findings suggest that IFN-alpha alone promptly generates nondendritic APCs able to stimulate memory immune responses. This may represent an additional mode of action of IFN-alpha in vivo.
Gerlini
Gianni
G
Plastic Surgery Unit, Regional Melanoma Referral Center, Tuscan Tumor Institute (ITT), Santa Maria Annunziata Hospital, Florence, Italy. g.gerlini@dfc.unifi.it
Mariotti
Giulia
G
Chiarugi
Alberto
A
Di Gennaro
Paola
P
Caporale
Roberto
R
Parenti
Astrid
A
Cavone
Leonardo
L
Tun-Kyi
Adrian
A
Prignano
Francesca
F
Saccardi
Riccardo
R
Borgognoni
Lorenzo
L
Pimpinelli
Nicola
N
D000938:Antigen-Presenting Cells; D015703:Antigens, CD; D018122:B7-1 Antigen; D015415:Biomarkers / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002644:Chickenpox / Q000276:immunology; D003713:Dendritic Cells; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007136:Immunoglobulins; D007156:Immunologic Memory / Q000187:drug effects; D016898:Interferon-alpha / Q000494:pharmacology*; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D000097802:CD83 Antigen
D015703:Antigens, CD; D018122:B7-1 Antigen; D015415:Biomarkers; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007136:Immunoglobulins; D016898:Interferon-alpha; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D000097802:CD83 Antigen