Reduced cytokine-mediated up-regulation of HLA-DR in TAP-deficient fibroblasts.
Human deficiency in transporter associated with antigen processing (TAP) is characterized by a very low surface expression of human leukocyte antigen (HLA) class I molecules in hematopoietic and non hematopoietic cells. Among the latter, TAP-deficient skin fibroblasts have previously been shown by us to be very sensitive to lysis by activated autologous NK cells, even in the presence of cytokines that up-regulate HLA class I expression, a mechanism sufficient to protect normal fibroblasts from NK cell-mediated killing. Our complementary investigations on two TAP-deficient skin fibroblast cell lines surprisingly revealed that in response to proinflammatory cytokines, up-regulation of HLA-DR molecules at the cell surface is much less marked than in the case of normal skin fibroblasts. In contrast, the surface molecules CD40 and CD54 increase as much as observed on normal cells, suggesting that TAP-deficient fibroblasts are able to efficiently transduce cytokine-mediated stimulating signals. Transfection of an intact TAP gene into one of the TAP-deficient fibroblast cell lines restored a normal HLA class I expression that strongly increased upon IFN-gamma-mediated stimulation, whereas HLA-DR still remained lower than in control cells. These results suggest that, in addition to the defect in the HLA class I antigen presentation pathway, HLA-DR up-regulation is affected in TAP-deficient skin fibroblasts through an unknown mechanism probably independent from TAP.
Zimmer
Jacques
J
Laboratoire d'Immunogénétique-Allergologie, Centre de Recherche Public de la Santé (CRP-Santé), 84 Val Fleuri, L-1526 Luxembourg, Luxembourg. jacques.zimmer@crp-sante.lu
Poli
Aurélie
A
Andrès
Emmanuel
E
Hanau
Daniel
D
Brons
Nicolaas H C
NH
Hentges
François
F
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology; D006684:HLA-DR Antigens / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D014162:Transfection; D015854:Up-Regulation
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D019013:CD40 Antigens; D016207:Cytokines; D006684:HLA-DR Antigens; D015395:Histocompatibility Antigens Class I; C073119:TAP1 protein, human; D018799:Intercellular Adhesion Molecule-1; C071692:TAP2 protein, human; D007371:Interferon-gamma