Major histocompatibility class I antigenic peptides derived from translation of pre-mRNAs generate immune tolerance

Ewa Maria Sroka, Mathilde Lavigne, Marika Pla, Chrysoula Daskalogianni, Maria Camila Tovar-Fernandez, Rodrigo Prado Martins, Bénédicte Manoury, Guillaume Darrasse-Jéze, Megane Nascimento, Sebastien Apcher, Robin Fåhraeus

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    4 Citations (Scopus)

    Résumé

    Antigenic peptides derived from introns are presented on major histocompatibility (MHC) class I molecules, but how these peptides are produced is poorly understood. Here, we show that an MHC class I epitope (SL8) sequence inserted in the second intron of the β-globin gene in a C57BL/6 mouse (HBB) generates immune tolerance. Introduction of SL8-specific CD8+ T cells derived from OT-1 transgenic mice resulted in a threefold increase in OT-1 T cell proliferation in HBB animals, as compared to wild-type animals. The growth of MCA sarcoma cells expressing the intron-derived SL8 epitope was suppressed in wild-type animals compared to HBB mice. The β-globin pre-mRNA was detected in the light polysomal fraction, and introducing stop codons identified a non-AUG initiation site between +228 and +255 nts upstream of the SL8. Isolation of ribosome footprints confirmed translation initiation within this 27 nt sequence. Furthermore, treatment with splicing inhibitor shifts the translation of the pre-mRNA to monosomal fractions and results in an increase of intron-derived peptide substrate as shown by polysome profiling and cell imaging. These results show that non-AUG-initiated translation of pre-mRNAs generates peptides for MHC class I immune tolerance and helps explain why alternative tissue-specific splicing is tolerated by the immune system.

    langue originaleAnglais
    Numéro d'articlee2208509120
    journalProceedings of the National Academy of Sciences of the United States of America
    Volume120
    Numéro de publication7
    Les DOIs
    étatPublié - 14 févr. 2023

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