Evidence of focusing the MHC class I immunopeptidome by tapasin

Abstract

Major Histocompatibility Complex class I (MHC-I) molecules bind and present
peptides to cytotoxic T cells, protecting against pathogens and cancer. MHC-I is
highly polymorphic and each allotype is promiscuous, and capable of binding a
unique and diverse repertoire of peptide ligands. The peptide editing chaperone
tapasin optimizes this allotype specific repertoire of peptides, resulting in the
selection of high affinity peptides. MHC-I allotypes differ in the extent they
engage tapasin. This suggests that tapasin-dependent MHC-I allotypes should
present a less diverse repertoire that is enriched in higher-affinity peptides, and
which are present in higher abundance, than tapasin independent MHC-I
allotypes, which should present a broader repertoire containing peptides with
a lower average affinity. Experimental verification of this hypothesis has been
confounded by the different peptide binding specificities of MHC-I allotypes.
Here, we independently investigated the peptide focusing function of tapasin by
introducing a point mutation into a tapasin independent MHC-I allotype that
dramatically increased its tapasin dependence without substantially altering its
peptide binding specificity. This allowed us to demonstrate ligand focusing by
tapasin at both the repertoire level in cellulo, and by using an in vitro system in
which tapasin was artificially tethered to MHC-I, at the individual peptide level.
We found that tapasin had a greater influence on tapasin dependent MHC-I
molecules, and that tapasin modulated peptide selection according to peptide-MHC-I complex stability, disfavoring short-lived peptide-MHC-I complexes.
Thus, tapasin dependent MHC-I molecules experience greater tapasin filtering,
resulting in less diverse MHC-I immunopeptidomes that are enriched in high
affinity peptide-MHC-I complexes.

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Identifiers

ORCID for Patrick Duriez: orcid.org/0000-0003-1814-2552

ORCID for Alistair Bailey: orcid.org/0000-0003-0023-8679

ORCID for Andy van Hateren: orcid.org/0000-0002-3915-0239

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