Études du ciblage intracellulaire des molécules non classiques du complexe majeur d'histocompatibilité de classe II

Motif di-leucine MIIC Chaîne Invariante Exosomes vi SUMMARY HLA-DM and HLA-DO are non-classical MHC class II molecules that modulate the loading of antigenic peptides on molecules such as HLA-DR in B ceils.HLA-DM catalyzes the peptide exchange and HLA-DO influences the peptide repertoire by negatively modulating the activity of HLA-DM.Peptide exchange occurs in class II-rich compartments of the endocytic pathway where they both accumulate.These compartments include multivesicular bodies in which HLA-DR and -DM interact at the level of the internai membranes.Although the targeting of HLA-DO to endosomal compartments is attributed to sorting information within DM cytoplasmic tau, we have investigated the presence of consensus sorting signais within the cytoplasmic domains of HLA DO.HLA-DR!DO chimeric and mutagenic molecuies were transfected into HeLa ceils.Our resuits show the presence of a functionai sorting motif within the beta chain.Interestingly, these resuits suggested that DO can modify DM sorting within endosomal compartments.This hypothesis was later demonstrated by others and prompted us to study the regulation of MVB/exosomal sorting of MHC moiecuies.Mature peptide-loaded HLA-DR moiecuies end-up at the ceil surface but aiso accumulate in exosomai vesicies.These small structures are shed presumably through the fusion of muitivesicuiar bodies with the plasma membrane and are obtained by high speed centrifugation of the culture medium.Despite their co localization with HLA-DR in MHC II-rich compartments, the presence of HLA-DM in exosomes remains to be demonstrated.In the second part of this work, we show by immunoblot that DM is present in exosomal fractions of the 721.45B lymphobiastoid celi une.A similar conclusion was reached when looking at exosomes from HeLa ceils transfected with CIITA.To gain insight into the intracellular mechanisms regulating exosome entry and cargo retention, HLA-DM was transfected into HeLa ceils.Interestingly, in these conditions, vii DM was excluded from exosomes.However, it was found in exosomes when its YXXL sorting motif was inactivated by site-directed mutagenesis or following co-expression of HLA-DR.Altogether, these resuits demonstrate that sorting signais in the cytoplasmic domains of transmembrane proteins can regulate exosome entry and raise the intriguing possibility that protein-protein interactions can moduiate the activity of such signais.xlii 4.1.7Ciblage du complexe DM-DO à la membrane limitante des MVBs17$ 4.1.7.1 Voie de transport du complexe DM/DO 17$ 4.1.7.2 Les motifs de ciblage de D0f3 17$ 4.1.7.3 Transport endosornique spécialisé 179 4.1.7.4 Rôle de HLA-DO dans le ciblage exosomale 180 4.2 Gestion du ciblage de HLA-DM aux exosomes par HLA-DR 180 4.2.1 Présence de HLA-DM aux fractions exosomales 181 4.2.2Absence de HLA-DM dans les exosomes des cellules HeLa DM.5 182 4.2.3Ciclage de HLA-DM aux exosornes par HLA-DR 182 4.2.4Rétention de HLA-DM à la membrane limitante du MVB et proscription de son entrée dans les membranes exosomales 183 4.2.5 Masquage du motif YXXL de HLA-DM 184 4.2.6 Intégration au radeau lipidique 184 4.2.6 Voie de ciblage indépendante de l'ubiquitine 185 4.2.7 Exosomes et dissémination de l'information antigénique 186 4.2.8Fonction de HLA-DO dans les membranes exosomales 18$ C II4.PI1RE 5 -. ....

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