Down-regulation of the expression and function of the transporter associated with antigen processing in murine tumor cell lines expressing IL-10.
The MHC class I molecules present antigenic peptides to CTL. The peptides are delivered to the secretory pathway by TAP, which is formed by the association of MHC-encoded TAP1 and TAP2 gene products. Tumor cells incubated or transfected with IL-10 had decreased but peptide-inducible expression of MHC class I, decreased sensitivity to MHC class I-restricted CTL, and increased NK sensitivity. We here demonstrate that IL-10 expression in the murine lymphoma RMA inhibits the TAP-dependent translocation of peptides to the endoplasmic reticulum, resulting in accumulation of immature MHC class I molecules in the endoplasmic reticulum and subsequently low expression of cell surface MHC class I molecules. This finding is explained by a down-regulation of expression of TAP1 and TAP2, observed in IL-10-transfected RMA cells as well as in IL-10-transfected P815 mastocytoma cells. In the J558L plasmacytoma cell line, constitutively expressing high levels of IL-10, increased TAP-dependent translocation of peptides and expression of cell surface MHC class I could be induced by IL-10 antisense expression. IL-10 is the first example to demonstrate that a cytokine can decrease the expression and function of the TAP1/2 molecular complex and, in more general terms, the first example of a cytokine with an inhibitory effect on MHC class I-mediated Ag presentation.
Salazar-Onfray
F
F
Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden. flavio.salazar@mtc.ki.se
Charo
J
J
Petersson
M
M
Freland
S
S
Noffz
G
G
Qin
Z
Z
Blankenstein
T
T
Ljunggren
H G
HG
Kiessling
R
R
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000276:immunology / Q000502:physiology*; D000818:Animals; D017951:Antigen Presentation; D001692:Biological Transport / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology*; D004721:Endoplasmic Reticulum / Q000276:immunology / Q000378:metabolism; D006183:H-2 Antigens / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology; D007113:Immunity, Innate; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology; D008223:Lymphoma; D012515:Mast-Cell Sarcoma; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000276:immunology / Q000494:pharmacology; D010954:Plasmacytoma; D011499:Protein Processing, Post-Translational; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection / Q000276:immunology; D014407:Tumor Cells, Cultured
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D006183:H-2 Antigens; D010455:Peptides; C073119:TAP1 protein, human; C486171:Tap1 protein, mouse; C489516:Tap2 protein, mouse; D016753:Interleukin-10; C071692:TAP2 protein, human