Characterisation of the ribosome generating peptides for major histocompatibility class I tolerance from pre-spliced mRNAs – PepTol
The proposal is based on strong preliminary data showing that translation of pre-spliced mRNAs generates peptides for immune tolerance for the major histocompatibility (MHC) class I pathway. We have introduced an antigenic peptide sequence (SL8 from chicken ovalbumin (Ova)) in the second intron of the B-globin gene in a C57BL/6 mouse (HBB) and can show that the animals are immune tolerant towards this epitope (Figure 1). We now propose to characterize the ribosome responsible for this non-canonical event translating pre-spliced mRNAs (see figure 2) and understand how it is regulated. This will have a major impact on i) understanding the immunological properties of mRNAs and give a better understanding of how the immune system is activated against RNA vaccines and explain the origin of intron-derived peptides presented on MHC class I molecules. This will ii) pave the way for controlling the production of antigenic peptide substrates for the MHC class I pathway and have implications for regulating the expression of antigens in autoimmune and cancer diseases. The outcome of this project will iii) describe a novel mRNA translation event that will help explain the physiological role of a previously demonstrated large pool of non-AUG initiated translation products (Ingolia et al., 2009).
We propose to characterize the ribosome responsible for translating pre-spliced mRNAs and how this event is regulated. The long term aim is to shed light on this non-canonical translation event and identify means by which the synthesis of MHC class I substrates can be manipulated. This will have important implication for designing vaccines and for understanding aspects of cancer immune evasion as well as autoimmune diseases.
Monsieur Robin Fahraeus (HEMATOPOIESE NORMALE ET PATHOLOGIQUE : EMERGENCE, ENVIRONNEMENT ET RECHERCHE TRANSLATIONNELLE)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
HEMATOPOIESE NORMALE ET PATHOLOGIQUE : EMERGENCE, ENVIRONNEMENT ET RECHERCHE TRANSLATIONNELLE
Help of the ANR 323,129 euros
Beginning and duration of the scientific project: September 2022 - 48 Months