Processing of tumor-associated antigen by the proteasomes of dendritic cells controls in vivo T-cell responses.
Dendritic cells are unique in their capacity to process antigens and prime naive CD8(+) T cells. Contrary to most cells, which express the standard proteasomes, dendritic cells express immunoproteasomes constitutively. The melanoma-associated protein Melan-A(MART1) contains an HLA-A2-restricted peptide that is poorly processed by melanoma cells expressing immunoproteasomes in vitro. Here, we show that the expression of Melan-A in dendritic cells fails to elicit T-cell responses in vitro and in vivo because it is not processed by the proteasomes of dendritic cells. In contrast, dendritic cells lacking immunoproteasomes induce strong anti-Melan-A T-cell responses in vitro and in vivo. These results suggest that the inefficient processing of self-antigens, such as Melan-A, by the immunoproteasomes of professional antigen-presenting cells prevents the induction of antitumor T-cell responses in vivo.
Chapatte
Laurence
L
Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland.
Ayyoub
Maha
M
Morel
Sandra
S
Peitrequin
Anne-Lise
AL
Lévy
Nicole
N
Servis
Catherine
C
Van den Eynde
Benoît J
BJ
Valmori
Danila
D
Lévy
Frédéric
F
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm; D003546:Cysteine Endopeptidases / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D008213:Lymphocyte Activation; D058965:MART-1 Antigen; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000276:immunology* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000951:Antigens, Neoplasm; D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; C548667:MLANA protein, human; C548668:Mlana protein, mouse; D009363:Neoplasm Proteins; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex