Major histocompatibility class I antigenic peptides derived from translation of pre-mRNAs generate immune tolerance - Immunologie-Immunopathologie-Immunothérapie Access content directly
Journal Articles Proceedings of the National Academy of Sciences of the United States of America Year : 2023

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

Rodrigo Prado Martins
Bénédicte Manoury

Abstract

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.

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Immunology
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Dates and versions

hal-04074191 , version 88 (19-04-2023)

Licence

Attribution - NonCommercial - NoDerivatives

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Ewa Maria Sroka, Mathilde Lavigne, Marika Pla, Chrysoula Daskalogianni, Maria Camila Tovar-Fernandez, et al.. Major histocompatibility class I antigenic peptides derived from translation of pre-mRNAs generate immune tolerance. Proceedings of the National Academy of Sciences of the United States of America, 2023, 120 (7), pp.e2208509120. ⟨10.1073/pnas.2208509120⟩. ⟨hal-04074191⟩
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