TY - JOUR
T1 - Major histocompatibility class I antigenic peptides derived from translation of pre-mRNAs generate immune tolerance
AU - Sroka, Ewa Maria
AU - Lavigne, Mathilde
AU - Pla, Marika
AU - Daskalogianni, Chrysoula
AU - Tovar-Fernandez, Maria Camila
AU - Martins, Rodrigo Prado
AU - Manoury, Bénédicte
AU - Darrasse-Jéze, Guillaume
AU - Nascimento, Megane
AU - Apcher, Sebastien
AU - Fåhraeus, Robin
N1 - Publisher Copyright:
Copyright © 2023 the Author(s).
PY - 2023/2/14
Y1 - 2023/2/14
N2 - 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.
AB - 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.
KW - MHC class I antigen presentation
KW - immune tolerance
KW - mRNA translation
UR - http://www.scopus.com/inward/record.url?scp=85147460949&partnerID=8YFLogxK
U2 - 10.1073/pnas.2208509120
DO - 10.1073/pnas.2208509120
M3 - Article
C2 - 36745791
AN - SCOPUS:85147460949
SN - 0027-8424
VL - 120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 7
M1 - e2208509120
ER -