From Chickens to Humans: The Importance of Peptide Repertoires for MHC Class I Alleles

Abstract

In humans, killer immunoglobulin-like receptors (KIRs), expressed on natural killer (NK) and thymus-derived (T) cells, and their ligands, primarily the classical class I molecules of the major histocompatibility complex (MHC) expressed on nearly all cells, are both polymorphic. The variation of this receptor-ligand interaction, based on which alleles have been inherited, is known to play crucial roles in resistance to infectious disease, autoimmunity, and reproduction in humans. However, not all the variation in response is inherited, since KIR binding can be affected by a portion of the peptide bound to the class I molecules, with the particular peptide presented affecting the NK response. The extent to which the large multigene family of chicken immunoglobulin-like receptors (ChIRs) is involved in functions similar to KIRs is suspected but not proven. However, much is understood about the two MHC-I molecules encoded in the chicken MHC. The BF2 molecule is expressed at a high level and is thought to be the predominant ligand of cytotoxic T lymphocytes (CTLs), while the BF1 molecule is expressed at a much lower level if at all and is thought to be primarily a ligand for NK cells. Recently, a hierarchy of BF2 alleles with a suite of correlated properties has been defined, from those expressed at a high level on the cell surface but with a narrow range of bound peptides to those expressed at a lower level on the cell surface but with a very wide repertoire of bound peptides. Interestingly, there is a similar hierarchy for human class I alleles, although the hierarchy is not as wide. It is a question whether KIRs and ChIRs recognize class I molecules with bound peptide in a similar way, and whether fastidious to promiscuous hierarchy of class I molecules affect both T and NK cell function. Such effects might be different from those predicted by the similarities of peptide-binding based on peptide motifs, as enshrined in the idea of supertypes. Since the size of peptide repertoire can be very different for alleles with similar peptide motifs from the same supertype, the relative importance of these two properties may be testable.

Comparative analysis of the caecal tonsil transcriptome in two hen lines experimentally infected withSalmonellaEnteritidis

“…Eight of these genes have functions of interest: MHCIBF2, CLDN7, SIRT5, ENTPD1, SYT7, SLC22A23, S100B and MUC4 . The MHCIBF2 ( Major histocompatibility complex class I antigen BF2 ) gene is the predominant ligand of cytotoxic T lymphocytes [58]. It has been shown that a particular MHC I haplotype may contribute to control the response to SE infection in chicken [59,60].…”

PANDORA: A Fast, Anchor-Restrained Modelling Protocol for Peptide: MHC Complexes

“…The peptide is mainly anchored at the P1, P4, P6 and P9 pockets of MHC-II ( 19 , 21 ). Examples of non-canonical peptide anchor positions have been reported both for human pMHC-I ( 22 ) and pMHC-II ( 23 ), and for some other species’ pMHC-I ( 24 ).…”

Highly‐contiguous bovine genomes underpin accurate functional analyses and updated nomenclature of MHC class I

“…Recently a correlation has been identified between the expression level of BF2 alleles and the diversity of their peptide repertoire. Alleles that are highly expressed have a narrower range of bound peptides (fastidious alleles) while the peptide repertoire is much broader in alleles with lower expression (promiscuous alleles) 12,13 . Humans have an essentially fixed number of three polymorphic classical (class Ia) genes, HLA‐A, B, and C, and three less‐polymorphic non‐classical (class Ib) genes, HLA‐E, F, and G—which are all known to interact with NK cell receptors 14–16 .…”

“…Taken together, different MHC class I alleles can have more dissimilar expression, peptide binding profiles, and ultimately functions than can currently be predicted by peptide binding motifs alone. Consequently, the concept of allele supertypes based on sequence alone likely contains an additional layer of complexity than has previously been considered 13 …”