Processing of tumor-associated antigen by the proteasomes of dendritic cells controls in vivo T-cell responses

Chapatte, Laurence [University of Lausanne, Epalinges, Switzerland] Ayyoub, Maha [Columbia University College of Physicians and Surgeons, New York (USA)] Morel, Sandra [UCL] Peitrequin, Anne-Lise [University of Lausanne, Epalinges, Switzerland] Lévy, Nicole [University of Lausanne, Epalinges, Switzerland] Servis, Catherine [University of Lausanne, Epalinges, Switzerland & ISREC, Epalinges, Switzerland] Van den Eynde, Benoît [UCL] Valmori, Danila [Columbia University College of Physicians and Surgeons, New York (USA)] Lévy, Frédéric [University of Lausanne, Epalinges, Switzerland & ISREC, Epalinges, Switzerland] et al.[show all]

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.