Regulatory role of tryptophan degradation pathway in HLA-G expression by human monocyte-derived dendritic cells.
Dendritic cells (DC) are strong inducers of immunity but they can also be tolerogenic. During monocyte differentiation to DC the immunosuppressive indoleamine-2,3-dioxygenase (IDO) is induced. IDO degrades Trp to kynurenine, which is further metabolized to 3-hydroxyanthranilic acid. DC can also express mRNA and protein of the tolerogenic molecule HLA-G, but there is no surface expression. We studied the effect of the Trp degrading pathway on HLA-G expression by DC. When monocytes were differentiated to immature DC in presence of either Trp or its metabolites kynurenine or 3-hydroxyanthranilic acid they expressed cell surface HLA-G, and Trp also increased shedding of HLA-G1. Trp induced HLA-G cell surface expression when present during maturation with IFN-gamma+LPS, but not with TNF-alpha. Kynurenine increased HLA-G expression in both TNF-alpha and IFN-gamma+LPS matured DC, and 3-hydroxyanthranilic acid had a very weak effect on HLA-G cell surface expression when present during maturation. Shedding of HLA-G1 was more pronounced in IFN-gamma+LPS-matured DC than in immatured DC. Maturation with IFN-gamma+LPS in presence of kynurenine also increased HLA-G5 secretion. The mechanism involved seems to be post-translational as mRNA and cellular HLA-G protein content was not increased with Trp, kynurenine or 3-hydroxyanthranilic acid treatments. Finally, immature DC preincubated with Trp, kynurenine and 3-hydroxyanthranilic acid have after a decreased capacity to stimulate T cells in mixed lymphocyte reaction. In IFN-gamma+LPS-matured DC this decreased capacity was obtained with kynurenine and 3-hydroxyanthranilic acid. These results suggest that IDO can induce HLA-G cell surface expression in DC, and that these two molecules can cooperate in the immune suppression.
López
Ana S
AS
Department of Clinical Biochemistry, Clínica Universitaria de Navarra, Av. Pío XII 36, 31008 Pamplona, Spain.
Alegre
Estibaliz
E
LeMaoult
Joël
J
Carosella
Edgardo
E
González
Alvaro
A
D015095:3-Hydroxyanthranilic Acid / Q000378:metabolism; D045744:Cell Line, Tumor; D002469:Cell Separation; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D006680:HLA Antigens / Q000235:genetics* / Q000378:metabolism; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology; D007737:Kynurenine / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D009000:Monocytes / Q000166:cytology; D011499:Protein Processing, Post-Translational; D013601:T-Lymphocytes / Q000276:immunology; D014364:Tryptophan / Q000378:metabolism*
D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008070:Lipopolysaccharides; D015095:3-Hydroxyanthranilic Acid; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan