Surface expression, peptide repertoire, and thermostability of chicken class I molecules correlate with peptide transporter specificity

Abstract

The chicken major histocompatibility complex (MHC) has strong genetic associations with resistance and susceptibility to certain infectious pathogens. The cell surface expression level of MHC class I molecules varies as much as 10-fold between chicken haplotypes and is inversely correlated with diversity of peptide repertoire and with resistance to Marek's disease caused by an oncogenic herpesvirus. Here we show that the average thermostability of class I molecules isolated from cells also varies, being higher for high-expressing MHC haplotypes. However, we find roughly the same amount of class I protein synthesized by high-and low-expressing MHC haplotypes, with movement to the cell surface responsible for the difference in expression. Previous data show that chicken TAP genes have high allelic polymorphism, with peptide translocation specific for each MHC haplotype. Here we use assembly assays with peptide libraries to show that high-expressing B15 class I molecules can bind a much wider variety of peptides than are found on the cell surface, with the B15 TAPs restricting the peptides available. In contrast, the translocation specificity of TAPs from the low-expressing B21 haplotype is even more permissive than the promiscuous binding shown by the dominantly expressed class I molecule. B15/B21 heterozygote cells show much greater expression of B15 class I molecules than B15/B15 homozygote cells, presumably as a result of receiving additional peptides from the B21 TAPs. Thus, chicken MHC haplotypes vary in several correlated attributes, with the most obvious candidate linking all these properties being molecular interactions within the peptideloading complex (PLC).ABC transporter | restrictive | permissive | heterozygous advantage | overdominance

Whole genome duplications have provided teleosts with many roads to peptide loaded MHC class I molecules

“…The chicken tapasin and TAP genes are polymorphic with each unique BF2, TAP1, TAP2 and TAPBP combination segregating as a stable functional haplotype. TAPBP and TAP polymorphism govern the peptides available for binding to the BF2 allele [ 24 , 25 ]. Thus BF2 alleles in heterozygous animals can in theory bind peptides pumped by both haplotypes as opposed to alleles in homozygous animals, thus broadening the MHCIa peptide repertoire.…”

“…Presumably, presenting a larger repertoire of pathogen epitopes activate a wider range of T cell clones, a response needed for protection against this pathogen. To counteract against inducing autoimmune reactions, the MHCIa molecules with a wide peptide binding repertoire are only present in low copy numbers on the cell surface while MHCIa molecules with a narrow peptide repertoire are much higher expressed on the cell surface [ 24 , 25 ]. A similar picture was described in humans, where also here lower surface expression levels corresponded with a broader peptide binding ability.…”

An Invariant Arginine in Common with MHC Class II Allows Extension at the C-Terminal End of Peptides Bound to Chicken MHC Class I

“…Compared with mammals, the chicken MHC is simple and compact, with only the class I molecule encoded by the BF2 locus expressed at a high level (17)(18)(19). The reason for this dominantly expressed class I molecule is the fact that the chicken MHC, in stark contrast to the MHC of typical mammals, suffers very little recombination and encodes polymorphic peptide-loading complex molecules, including TAPs and tapasin, which, for each haplotype, coevolve with the particular BF2 allele present (20)(21)(22)(23).…”

Improved Transgenic Mouse Model for Studying HLA Class I Antigen Presentation

“…Previous studies of human or animal TAP transportation demonstrate that the TAP complex selects peptides with preferential sequences, and TAP binding affinity has a significant impact on epitope presentation 16 17 18 19 20 21 . A minimal TAP affinity is required for peptide presentation.…”