L'absence d'apprêtement de certains antigènes par l'immunoprotéasome empêche leur présentation par les cellules dendritiques
(2000)
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- By stimulating human t lymphocytes with an autologous renal carcinoma cell line, we obtained CTL recognizing an antigen composed of a peptide presented by HLA-B51 and derived form a novel, ubiquitous protein called RU1. Surprisingly, the CTL failed to lyse the autologous EBV-transformed B cell (EBV-B cells), event though the latter expressed the RU1 protein. To explain this paradox, we studied the processing of the RU1/HLA-B51 antigen by proteasomes from tumor cells or from EBV-B cells. Digestions of a precursor peptide encompassing the antigenic épitope were performed in vitro with purified proteasomes. The digests were then tested for recognition by the CTL, and analyser by HPLC and mass spectrometry. We hence determined that the proteasomes from the tumor cells, which are composed of standard proteasome, can produce the antigenic peptide, whereas EBV-B cells proteasomes, which are mainly composed of immunoproteasome, cannot. This difference results from the constitutive expression of the immunoproteasome by the EBV-B cells. This supported by the observation that an IFNγ treatment of the tumor cells, which induces immunoproteasome expression in these cells, results in their inability to process the RU1/HLA-B51 epitope and to be recognized by the anti RU1 CTL. The RU1/HLA-B51 antigen is the first épitope known to be processed by the standard proteasome but not by the immunoproteasome. We also showed that mature dendritic cells carry immunoproteasomes constitutively and fail to present the RU1/HLA-B51 antigen to the relevant CTL. This may explain why these CTL, although directed against an ubiquitous antigen, escape thymic selection and are not regularly activated in the periphery. <BR> The immunoproteasome is also less efficient than the standard proteasome at producing the melanoma differentiation antigen Melan-A26-35/HLA-A2, which is currently used for antitumoral vaccination. According to these data, we predict that, for immunization with such antigens poorly processed by immunoproteasome, proteins should be less efficient than peptides, as the latter do not require processing by the immunoproteasome of dendritic cells. <BR> We further showed that the presentation of a number of other tumoral and ubiquitous antigens is downregulated by the IFNγ treatment of the target cells. Extensive studies will be required to determine if this effect is due to a lack of processing by the induced immunoproteasome and to better appreciate to what extent the phenomenon we described here apply to other antigens
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Morel, S. (2000). L’absence d’apprêtement de certains antigènes par l’immunoprotéasome empêche leur présentation par les cellules dendritiques. https://hdl.handle.net/2078.5/111081