Page 395 - Avian Virology: Current Research and Future Trends

386 | Vervelde and Kaufman

The same is likely to be true for immune responses to other Antigen presentation by MHC molecules
pathogens and for antibody responses that are determined by There is molecular information reported for class I molecules
the single dominantly expressed class II molecule, but this is from normal cells of common chicken haplotypes, including
less well-studied. In contrast, typical mammals express a mul- eluted single self-peptides for BF1*02:01 and for BF2*02:01,
tigene family of classical MHC molecules. In an individual 04:01, 12:01, 14:01, 15:01, 19:01 and 21:01 (Wallny et al., 2006;
mammal, one or another of the MHC molecules will find a Chappell et al., 2015). There are pool sequences leading to pep-
protective peptide, so that overall each MHC haplotype confers tide motifs for the same molecules, except for BF2*21:01, which
more-or-less resistance to most pathogens, which reads out as remodels the binding site so much that the existing motif is clearly
weak genetic associations. incomplete (Kaufman et al., 1995; Wallny et al., 2006; Koch et
Genomic organization can explain reason why the chicken al., 2007; Chappell et al., 2015). There is also one study in which
MHC expresses a single class I molecule at a high level while BF2*04:01 (called BF2*13:01 in this study) and BF2*21:01
the typical mammalian MHC expresses a multigene family were expressed in the cell line RP9, which is heterozygous for
(Kaufman et al., 1999; Kaufman, 2015ab). The class I system is the B2 and B15 haplotypes; the eluted peptides were selected
spread very far across the MHC in mammals, with recombina- both by the TAP peptide-translocation specificities and the class
tion often separating the class I genes in the class I region from I peptide-binding specificities (Sherman et al., 2008). Finally,
the TAP and tapasin genes in the class II region. As a result, the there are crystal structures for self-peptides bound to BF2*02:01,
TAP and tapasin genes are monomorphic, providing peptides 04:01, 12:01, 14:01 and 21:01 (Koch et al., 2007; Zhang et al.,
and chaperone function for the class I multigene family as well 2012; Chappell et al., 2015; Xiao et al., 2018), which illustrate the
as whatever class I alleles appear by recombination. In contrast, molecular bases for the peptide motifs.
the chicken class I system is found within a small region and is Some class I-dependent responses to viruses in chickens have
rarely broken up by recombination, so that polymorphic TAP been assessed by several functional assays, including vaccination
and tapasin genes can co-evolve with the dominantly expressed against challenge. Initially, the effector cells from spleens of REV-
BF2 gene in stable haplotypes (Walker et al., 2011; van Hateren infected B2 chickens that killed REV-infected cells in vitro were
et al., 2013; Tregaskes et al., 2016). The TAP molecules encoded shown to be αβ rather than γδ T-cells (Merkle et al., 1992). Simi-
by a particular B haplotype have a peptide-translocation speci- larly, the effector cells from spleens of MDV-vaccinated B19 and
ficity that matches the peptide-binding specificity of the BF2 B21 chickens that killed REV-transformed cells transfected with
molecule of that haplotype (and the tapasin only interacts MDV genes were T-cells bearing CD8 and αβ of the TCR1 family
productively with the BF2 molecule of that haplotype). As a rather than CD4, αβ of the TCR2 family or γδ TCR (Omar and
result, the BF2 molecule is well-expressed with optimized pep- Schat 1997). In another approach, transfer of CD8 or αβ but not
tides, while the BF1 molecule with a different peptide-binding CD4 or γδ T-cells from IBV-infected chickens to naïve chickens
specificity may get few if any peptides and is therefore poorly conferred resistance to challenge (Seo et al., 2000). However,
expressed and not used much in the immune response. early cytotoxic responses to MDV may reflect NK rather than
More recently, it has become clear that the B haplotypes T-cell responses (Garcia-Camacho et al., 2003), either due to NK
conferring resistance to MDV generally confer resistance to cell recognition of class I molecules (perhaps the BF1 molecule)
other viruses, due to a suite of properties that result in or to the presence of a NKR-P1 NK cell receptor called BNK in
dominantly expressed class I molecules with a wide peptide the BF-BL region (Kaufman et al., 1999; Rogers et al., 2008; Kim
repertoire but low cell surface expression (Chappell et al., et al., 2018).
2015; Kaufman, 2015b, 2018). The B2 and B21 haplotypes In many cases the target MHC molecule and even the peptides
that encode highly promiscuous BF2 alleles have been over- involved have been determined. For instance, lysis of MDV- and
whelmingly reported as the haplotypes that confer resistance ALV-infected target cells from the B21 haplotype were shown to
to economically important viruses, and even moderately pro- depend on the classical class I molecule BF2 (Fulton et al., 1995;
miscuous alleles such as those encoded by the B6 and B12 Thacker et al., 1995). Vaccination of B12 chickens with an RSV
haplotypes generally protect compared with more fastidious peptide (predicted on the basis of a peptide motif and shown to
alleles from the B4/B13, B15 and B19 haplotypes. It appears bind BF2*12:01) was reported to protect from tumours after viral
that the poorly expressed promiscuous alleles act as general- challenge (Hofmann et al., 2003). Similarly, a molecular defined
ists, protecting from a wide variety of common viruses. The vaccine (based on an IBDV VP2 fusion protein delivered by a FPV
well-expressed fastidious alleles with peptide-binding specifici- vector) protected B12 chickens from Gumboro disease (Butter et
ties that are much more stringent may act like specialists al., 2013). A variety of peptides from AIV (predicted on the basis
that are important for particular new or virulent pathogens, of published motifs for BF2*04:01, 12:01, 15:01 and 19:01) were
in the same way as the fastidious HLA-B*57:01, 58:01 and found to stimulate IFNγ secretion (as assessed by enzyme-linked
27:05 confer slow progression from human immunodeficiency immunospot assays, or ELISpots) from lung lymphocytes from
virus (HIV) infection to frank acquired immune deficiency infected chickens (Reemers et al., 2012). The same four motifs
syndrome (AIDS) (Kaufman, 2018). Clearly, much more were used to predict peptides from AIV and IBV, and some were
research is needed to determine the extent to which this found to stimulate in vitro responses, as assessed by ELIspot and
new idea is true, and to understand the mechanisms and the CD8 cell proliferation assays, from spleen lymphocytes from vac-
consequences. cinated chickens; for IBD vaccination with some of the peptide