Generalists and Specialists: A New View of How MHC Class I Molecules Fight Infectious Pathogens
Authors: Jim Kaufman
Journal: Trends in Immunology (2018)

A broad overview of classical MHC I expression and bound peptides reveals an inverse correlation between repertoire breadth and cell-surface expression in some chicken and human alleles. Several chicken class I alleles with wide peptide-binding repertoires (promiscuity) are associated with resistance to a variety of common diseases. Conversely, a narrow peptide-binding repertoire (fastidiousness) in some human HLA-B alleles is associated with resistance to HIV progression. Cell-surface expression of some classical class I alleles depends on the regulation of translocation to the cell surface rather than of transcription or translation. MHC translocation is influenced by peptide translocation in chickens and by tapasin interaction in humans. In comparison with the major histocompatibility complexes (MHCs) of typical mammals, the chicken MHC is simple and compact with a single dominantly expressed class I molecule that can determine the immune response. In addition to providing useful information for the poultry industry and allowing insights into the evolution of the adaptive immune system, the simplicity of the chicken MHC has allowed the discovery of phenomena that are more difficult to discern in the more complicated mammalian systems. This review discusses the new concept that poorly expressed promiscuous class I alleles act as generalists to protect against a wide variety of infectious pathogens, while highly expressed fastidious class I alleles can act as specialists to protect against new and dangerous pathogens. In comparison with the major histocompatibility complexes (MHCs) of typical mammals, the chicken MHC is simple and compact with a single dominantly expressed class I molecule that can determine the immune response. In addition to providing useful information for the poultry industry and allowing insights into the evolution of the adaptive immune system, the simplicity of the chicken MHC has allowed the discovery of phenomena that are more difficult to discern in the more complicated mammalian systems. This review discusses the new concept that poorly expressed promiscuous class I alleles act as generalists to protect against a wide variety of infectious pathogens, while highly expressed fastidious class I alleles can act as specialists to protect against new and dangerous pathogens. An enormous body of knowledge about the MHC and MHC molecules has been amassed over the past 50 years, mostly due to work on humans and important biomedical model species like mice [1Klein J. The Natural History of the Major Histocompatibility Complex. Wiley, 1986Google Scholar]. This information is extremely detailed, complex but well integrated, and crucially important both for basic scientific understanding of immune and autoimmune responses and for practical medical applications, including transplantation [2Trowsdale J. Knight J.C. Major histocompatibility complex genomics and human disease.Annu. Rev. Genomics Hum. Genet. 2013; 14: 301-323Crossref PubMed Scopus (407) Google Scholar, 3Tiercy J.M. Claas F. Impact of HLA diversity on donor selection in organ and stem cell transplantation.Hum. Hered. 2013; 76: 178-186Crossref PubMed Scopus (27) Google Scholar]. What is the point of trying to understand the MHC in non-mammalian vertebrates, when there is such rich and relevant knowledge for placental mammals? Besides the obvious importance to disease resistance and vaccination in poultry [4Kaufman J. The avian MHC.in: Schat K.A. Avian Immunology. 2nd edn. Elsevier, 2014: 149-167Crossref Scopus (25) Google Scholar, 5Miller M.M. Taylor R.L. Brief review of the chicken major histocompatibility complex: the genes, their distribution on chromosome 16, and their contributions to disease resistance.Poult. Sci. 2016; 95: 375-392Crossref PubMed Scopus (94) Google Scholar], research into the chicken MHC has led to novel insights about the evolution of the adaptive immune system [6Kaufman J. The evolutionary origins of the adaptive immune system of jawed vertebrates.in: Kaufmann S.H.E. The Immune Response to Infection. American Society of Microbiology Press, 2011: 41-54Crossref Google Scholar, 7Kaufman J. Antigen processing and presentation: evolution from a bird's eye view.Mol. Immunol. 2013; 55: 159-161Crossref PubMed Scopus (37) Google Scholar, 8Kaufman J. What chickens would tell you about the evolution of antigen processing and presentation.Curr. Opin. Immunol. 2015; 34: 35-42Crossref PubMed Scopus (25) Google Scholar, 9Kaufman, J. Unfinished business: the evolution of the MHC and the adaptive immune system of jawed vertebrates. Annu. Rev. Immunol. (in press)Google Scholar]. This short review highlights a third advantage: how the simplicity (at least in some senses) of the chicken MHC has permitted the discovery and/or study of phenomena that have been more difficult to discern in the complex MHC biology of humans and other typical mammals. It is generally accepted that the high level of allelic polymorphism of MHC classical class I and class II genes is driven by a molecular arms race with pathogens [10Bernatchez L. Landry C. MHC studies in nonmodel vertebrates: what have we learned about natural selection in 15 years?.J. Evol. Biol. 2003; 16: 363-377Crossref PubMed Scopus (700) Google Scholar, 11Spurgin L.G. Richardson D.S. How pathogens drive genetic diversity: MHC, mechanisms and misunderstandings.Proc. Biol. Sci. 2010; 277: 979-988Crossref PubMed Scopus (528) Google Scholar]. An expectation from this relationship is that particular MHC alleles would confer resistance or susceptibility to particular infectious pathogens. The human MHC does have many strong genetic associations with autoimmune disease, but the reported associations with infectious disease are much weaker [2Trowsdale J. Knight J.C. Major histocompatibility complex genomics and human disease.Annu. Rev. Genomics Hum. Genet. 2013; 14: 301-323Crossref PubMed Scopus (407) Google Scholar, 12Hill A.V. The immunogenetics of human infectious diseases.Annu. Rev. Immunol. 1998; 16: 593-617Crossref PubMed Scopus (467) Google Scholar]. In essence, it has taken the best immunologists, epidemiologists, and geneticists decades to provide convincing evidence for such genetic associations. The best-studied example is the slow progression of HIV infection to AIDS conferred by the presence of certain HLA-B alleles as well as the cell-surface expression levels of HLA-C alleles [13Goulder P.J. Walker B.D. 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The MHC encoding classical class I and class II molecules is one region (the so-called BF-BL region) in this B locus [16Kaufman J. et al.The chicken B locus is a minimal essential major histocompatibility complex.Nature. 1999; 401: 923-925Crossref PubMed Scopus (506) Google Scholar]; nearby are regions with CD1 genes, TRIM genes, and the mysterious BG genes that have some similarities to butyrophilins [4Kaufman J. The avian MHC.in: Schat K.A. Avian Immunology. 2nd edn. Elsevier, 2014: 149-167Crossref Scopus (25) Google Scholar, 5Miller M.M. Taylor R.L. Brief review of the chicken major histocompatibility complex: the genes, their distribution on chromosome 16, and their contributions to disease resistance.Poult. Sci. 2016; 95: 375-392Crossref PubMed Scopus (94) Google Scholar]. Initially, these associations were with responses to oncogenic viral diseases such as Marek's disease and Rous sarcoma, with the B locus determining life or death for individual chickens. Now there is a long list of viruses, bacteria, and even parasites that have significant associations with the BF-BL region [4Kaufman J. The avian MHC.in: Schat K.A. Avian Immunology. 2nd edn. Elsevier, 2014: 149-167Crossref Scopus (25) Google Scholar, 5Miller M.M. Taylor R.L. Brief review of the chicken major histocompatibility complex: the genes, their distribution on chromosome 16, and their contributions to disease resistance.Poult. Sci. 2016; 95: 375-392Crossref PubMed Scopus (94) Google Scholar, 17Psifidi A. et al.Genome-wide association studies of immune, disease and production traits in indigenous chicken ecotypes.Genet. Sel. Evol. 2016; 48: 74Crossref PubMed Scopus (32) Google Scholar, 18Psifidi A. et al.The genomic architecture of resistance to Campylobacter jejuni intestinal colonisation in chickens.BMC Genomics. 2016; 17: 293Crossref PubMed Scopus (26) Google Scholar]. Compared with the MHC of typical mammals, the BF-BL region of chickens (also sometimes called the 'classical MHC' or the 'core MHC') is compact, simple, and arranged differently (Figure 1), with two class II B (so-called BLB) genes flanking the tapasin gene located near the DM genes followed by a pair of class I (so-called BF) genes that flank the TAP genes and, finally, the class III region genes [16Kaufman J. et al.The chicken B locus is a minimal essential major histocompatibility complex.Nature. 1999; 401: 923-925Crossref PubMed Scopus (506) Google Scholar]. Moreover, no recombination within the BF-BL region has been observed in experiments [19Hala K. et al.A new recombinant allele in the B complex of the chicken.Folia Biol. 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The monomorphic DR-like class II A gene (BLA) is located some 5 cM away [29Salomonsen J. et al.The properties of the single chicken MHC classical class II alpha chain (B-LA) gene indicate an ancient origin for the DR/E-like isotype of class II molecules.Immunogenetics. 2003; 55: 605-614Crossref PubMed Scopus (55) Google Scholar], the monomorphic β2-microglobulin (β2m) gene is on a different chromosome [30Riegert P. et al.The chicken β2-microglobulin gene is located on a non-major histocompatibility complex microchromosome: a small, G+C-rich gene with X and Y boxes in the promoter.Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 1243-1248Crossref PubMed Scopus (54) Google Scholar, 31Jones C.T. et al.Gene homologs on human chromosome 15q21–q26 and a chicken microchromosome identify a new conserved segment.Mamm. Genome. 1997; 8: 436-440Crossref PubMed Scopus (31) Google Scholar], and inducible proteasome (LMP/PSMB) genes have not been found in the genome [32Erath S. Groettrup M. No evidence for immunoproteasomes in chicken lymphoid organs and activated lymphocytes.Immunogenetics. 2015; 67: 51-60Crossref PubMed Scopus (16) Google Scholar]. Thus, the polymorphic classical class I and class II B genes are in strong linkage disequilibrium with polymorphic peptide-loading genes, leading to relatively stable MHC haplotypes of polymorphic coevolving genes [33Kaufman J. et al.A "minimal essential MHC" and an "unrecognized MHC": two extremes in selection for polymorphism.Immunol. Rev. 1995; 143: 63-88Crossref PubMed Scopus (237) Google Scholar, 34Kaufman J. Co-evolution with chicken class I genes.Immunol. Rev. 2015; 267: 56-71Crossref PubMed Scopus (25) Google Scholar]. This coevolution is clearly seen in the chicken class I system, in which the specificity of peptide translocation by the TAP alleles correlates with the peptide motif of the class I molecule encoded by the BF2 (but not the BF1) gene [27Walker B.A. et al.The dominantly expressed class I molecule of the chicken MHC is explained by coevolution with the polymorphic peptide transporter (TAP) genes.Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 8396-8401Crossref PubMed Scopus (72) Google Scholar, 34Kaufman J. Co-evolution with chicken class I genes.Immunol. Rev. 2015; 267: 56-71Crossref PubMed Scopus (25) Google Scholar, 35Tregaskes C.A. et al.Surface expression, peptide repertoire, and thermostability of chicken class I molecules correlate with peptide transporter specificity.Proc. Natl. Acad. Sci. U. S. A. 2016; 113: 692-697Crossref PubMed Scopus (21) Google Scholar]. Thus, the BF2 class I molecule receives lots of peptides whereas the BF1 molecule gets far fewer peptides and might be expected to have become much less important for antigen presentation. The BF1 gene has suffered deletions and insertions leading to far less expression at the RNA and protein levels than the BF2 gene [36Shaw I. et al.Different evolutionary histories of the two classical class I genes BF1 and BF2 illustrate drift and selection within the stable MHC haplotypes of chickens.J. Immunol. 2007; 178: 5744-5752Crossref PubMed Scopus (68) Google Scholar, 37Wallny H.J. et al.Peptide motifs of the single dominantly expressed class I molecule explain the striking MHC-determined response to Rous sarcoma virus in chickens.Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 1434-1439Crossref PubMed Scopus (154) Google Scholar]. Most importantly, the peptides presented by the dominantly expressed BF2 molecule can explain the immune response to certain economically important viruses and vaccines [37Wallny H.J. et al.Peptide motifs of the single dominantly expressed class I molecule explain the striking MHC-determined response to Rous sarcoma virus in chickens.Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 1434-1439Crossref PubMed Scopus (154) Google Scholar, 38Koch M. et al.Structures of an MHC class I molecule from B21 chickens illustrate promiscuous peptide binding.Immunity. 2007; 27: 885-899Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 39Butter C. et al.The peptide motif of the single dominantly expressed class I molecule of the chicken MHC can explain the response to a molecular defined vaccine of infectious bursal disease virus (IBDV).Immunogenetics. 2013; 65: 609-618Crossref PubMed Scopus (23) Google Scholar]. Such a system of coevolving alleles is not found in most placental mammals. In humans and other typical mammals, the antigen-processing and peptide-loading genes are located in the class II and extended class II regions, far from the class I genes that they serve [40MHC Sequencing Consortium Complete sequence and gene map of a human major histocompatibility complex.Nature. 1999; 401: 921-923Crossref PubMed Scopus (922) Google Scholar]. Thus, alleles of antigen-processing and peptide-loading genes that were advantageous for any particular class I allele would relatively rapidly be switched by recombination [41Carrington M. Recombination within the human MHC.Immunol. Rev. 1999; 167: 245-256Crossref PubMed Scopus (96) Google Scholar] and any advantage lost. There are few sequence alleles of TAP, tapasin, and inducible proteasome components and these appear to be functionally monomorphic [42Momburg F. et al.Selectivity of MHC-encoded peptide transporters from human, mouse and rat.Nature. 1994; 367: 648-651Crossref PubMed Scopus (304) Google Scholar, 43Obst R. et al.TAP polymorphism does not influence transport of peptide variants in mice and humans.Eur. J. Immunol. 1995; 25: 2170-2176Crossref PubMed Scopus (74) Google Scholar, 44Williams A.P. et al.Identification of novel tapasin polymorphisms and linkage disequilibrium to MHC class I alleles.Immunogenetics. 2000; 52: 9-11Crossref PubMed Scopus (13) Google Scholar], working as average best fits to provide peptides for all class I molecules regardless of locus or allele. This situation allows a multigene family of class I genes all of which are (or can be, for HLA-C) relatively well expressed. To be clear, there are mammals (like rats) for which the classical class I genes have moved close to the antigen-processing and peptide-loading genes, with the result that one of the TAP genes is oligomorphic and coevolves with the class I molecules [45Joly E. et al.Co-evolution of rat TAP transporters and MHC class I RT1-A molecules.Curr. Biol. 1998; 8: 169-172Abstract Full Text Full Text PDF PubMed Google Scholar]. The difference in the number of class I loci that encode well-expressed class I molecules provides at least part of the explanation for the difference between the human and the chicken MHC in genetic association with infectious disease [4Kaufman J. The avian MHC.in: Schat K.A. Avian Immunology. 2nd edn. Elsevier, 2014: 149-167Crossref Scopus (25) Google Scholar, 33Kaufman J. et al.A "minimal essential MHC" and an "unrecognized MHC": two extremes in selection for polymorphism.Immunol. Rev. 1995; 143: 63-88Crossref PubMed Scopus (237) Google Scholar]. In humans, if one class I molecule does not bind a protective peptide, it is likely that another one will, so that overall most MHC haplotypes confer more or less resistance to most pathogens, which reads out as low genetic association. In chickens, the single dominantly expressed class I molecule either finds a protective peptide from a particular pathogen or does not, and this life-and-death difference between haplotypes reads out as strong genetic association (Figure 2). Thus, the simplicity of the chicken MHC has allowed greater appreciation of this phenomenon of resistance to infectious disease. Why do chickens and typical mammals differ in the genomic organization of their MHCs, if the end result can be so dire for an individual chicken? The salient features of the chicken MHC class I system can be found in many if not most non-mammalian vertebrates [6Kaufman J. The evolutionary origins of the adaptive immune system of jawed vertebrates.in: Kaufmann S.H.E. The Immune Response to Infection. American Society of Microbiology Press, 2011: 41-54Crossref Google Scholar, 9Kaufman, J. Unfinished business: the evolution of the MHC and the adaptive immune system of jawed vertebrates. Annu. Rev. Immunol. (in press)Google Scholar, 46Kaufman J. Co-evolving genes in MHC haplotypes: the "rule" for nonmammalian vertebrates?.Immunogenetics. 1999; 50: 228-236Crossref PubMed Scopus (96) Google Scholar]. For example, ducks have polymorphic TAP genes next to five class I genes only one of which is expressed at a high level [47Moon D.A. et al.The MHC of the duck (Anas platyrhynchos) contains five differentially expressed class I genes.J. Immunol. 2005; 175: 6702-6712Crossref PubMed Scopus (79) Google Scholar, 48Mesa C.M. et al.The dominant MHC class I gene is adjacent to the polymorphic TAP2 gene in the duck, Anas platyrhynchos.Immunogenetics. 2004; 56: 192-203Crossref PubMed Scopus (50) Google Scholar]. Xenopus frogs have a single classical class I gene along with the TAP (apparently at least oligomorphic) and tapasin genes located together, with this class I region between the class II region and the class III region [49Ohta Y. et al.Ancestral organization of the MHC revealed in the amphibian Xenopus.J. Immunol. 2006; 176: 3674-3685Crossref PubMed Scopus (121) Google Scholar]. Atlantic salmon have a single classical class I gene close to the TAP2 gene, this region having a strong genetic association with resistance to at least one economically important virus [50Lukacs M.F. et al.Genomic organization of duplicated major histocompatibility complex class I regions in Atlantic salmon (Salmo salar).BMC Genomics. 2007; 8: 251Crossref PubMed Scopus (56) Google Scholar, 51Grimholt U. et al.MHC polymorphism and disease resistance in Atlantic salmon (Salmo salar); facing pathogens with single expressed major histocompatibility class I and class II loci.Immunogenetics. 2003; 55: 210-219Crossref PubMed Scopus (265) Google Scholar]. The organization originally discovered for chickens is likely to be the ancestral one. The genes for antigen processing, peptide loading, and antigen presentation are not closely related so they did not evolve by gene duplication and acquisition of new functions. Instead, unrelated genes coevolved to work together as a pathway, and such coevolution is favored by close linkage. In other words, the genes of the class I system, and by extension the class II system, T cell receptors, and natural killer (NK) cell receptors, are likely to have emerged in one region, a primordial MHC, that has been falling apart ever since [6Kaufman J. The evolutionary origins of the adaptive immune system of jawed vertebrates.in: Kaufmann S.H.E. The Immune Response to Infection. American Society of Microbiology Press, 2011: 41-54Crossref Google Scholar, 9Kaufman, J. Unfinished business: the evolution of the MHC and the adaptive immune system of jawed vertebrates. Annu. Rev. Immunol. (in press)Google Scholar]. In support of this notion, genes found in various locations around the genome of mammals are found in or near the MHC of non-mammalian vertebrates. For example, the genes for an NK cell receptor and putative ligand (BNK and Blec, like NKR-P1 and LLT1/clr) are found in the chicken MHC rather than in the region syntenic to the NK complex (NKC) as in mammals [16Kaufman J. et al.The chicken B locus is a minimal essential major histocompatibility complex.Nature. 1999; 401: 923-925Crossref PubMed Scopus (506) Google Scholar, 52Rogers S.L. et al.Characterization of the chicken C-type lectin-like receptors B-NK and B-lec suggests that the NK complex and the MHC share a common ancestral region.J. Immunol. 2005; 174: 3475-3483Crossref PubMed Scopus (69) Google Scholar]. Thus, it is the mammalian MHC that is novel, and the MHC of at least one marsupial is organized like that of chickens [53Belov K. et al.Reconstructing an ancestral mammalian immune supercomplex from a marsupial major histocompatibility complex.PLoS Biol. 2006; 4: e46Crossref PubMed Scopus (129) Google Scholar], so the change occurred in the lineage leading to placental mammals [6Kaufman J. The evolutionary origins of the adaptive immune system of jawed vertebrates.in: Kaufmann S.H.E. The Immune Response to Infection. American Society of Microbiology Press, 2011: 41-54Crossref Google Scholar, 9Kaufman, J. Unfinished business: the evolution of the MHC and the adaptive immune system of jawed vertebrates. Annu. Rev. Immunol. (in press)Google Scholar, 27Walker B.A. et al.The dominantly expressed class I molecule of the chicken MHC is explained by coevolution with the polymorphic peptide transporter (TAP) genes.Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 8396-8401Crossref PubMed Scopus (72) Google Scholar]. A potential mechanistic explanation for this change would be an inversion (Figure 3) that brought the class III region into the center of the MHC and swung the class I genes to the outside, with the breakpoint such that the antigen-processing and peptide-loading genes were left behind and eventually became part of the class II region. As discussed above, sufficient levels of recombination meant that advantageous combinations of genes could not stay together, and the TAP, tapasin, and inducible proteasome genes became average best fits for whatever class I allele appeared by recombination. Once many alleles could be serviced, a multigene family became possible. Some associations with the chicken MHC could be easily explained by the BF2 class I allele from a resistant (but not a susceptible) chicken finding a protective peptide [37Wallny H.J. et al.Peptide motifs of the single dominantly expressed class I molecule explain the striking MHC-determined response to Rous sarcoma virus in chickens.Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 1434-1439Crossref PubMed Scopus (154) Google Scholar, 39Butter C. et al.The peptide motif of the single dominantly expressed class I molecule of the chicken MHC can explain the response to a molecular defined vaccine of infectious bursal disease virus (IBDV).Immunogenetics. 2013; 65: 609-618Crossref PubMed Scopus (23) Google Scholar], but the strong associations with Marek's disease were more challenging to explain. Marek's disease virus (MDV), an oncogenic herpes virus with a complex life cycle and significant evolution of virulence in historic times, has been an enormous economic problem [54Osterrieder N. et al.Marek's disease virus: from miasma to model.Nat. Rev. Microbiol. 2006; 4: 283-294Crossref PubMed Scopus (315) Google Scholar]. It was unclear how the MHC might confer susceptibility, since any class I molecule would be expected to bind a protective peptide from at least one of the 100 MDV genes. However, MHC haplotypes like B19 were strongly associated with susceptibility while B2 and B21 were strongly associated with resistance [55Plachy J. et al.Biology of the chicken MHC (B complex).Crit. Rev. Immunol. 1992; 12: 47-79PubMed Google Scholar]. It has become clear that the BF2 molecules from susceptible haplotypes have peptide motifs much like those of typical mammalian class I molecules, with several pockets in the binding groove each one of which binds only one or a few similar amino acids [37Wallny H.J. et al.Peptide motifs of the single dominantly expressed class I molecule explain the striking MHC-determined response to Rous sarcoma virus in chickens.Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 1434-1439Crossref PubMed Scopus (154) Google Scholar, 56Zhang J. et al.Narrow groove and restricted anchors of MHC class I molecule BF2*0401 plus peptide transporter restriction can explain disease susceptibility of B4 chickens.J. Immunol. 2012; 189: 4478-4487Crossref PubMed Scopus (46) Google Scholar]. Such class I molecules might be called fastidious, with stringent peptide motifs and narrow peptide repertoires. By contrast, the BF2 molecules from resistant haplotypes can bind an exceedingly large variety of peptides and might be called promiscuous, with relaxed peptide motifs and wide peptide repertoires [38Koch M. et al.Structures of an MHC class I molecule from B21 chickens illustrate promiscuous peptide binding.Immunity. 2007; 27: 885-899Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 57Chappell P. et al.Expression levels of MHC class I molecules are inversely correlated with promiscuity of peptide binding.Elife. 2015; 4e05345Crossref PubMed Scopus (83) Google Scholar]. For instance, the molecule BF2*21:01 remodels the binding site to accommodate three anchor residues, at peptide positions P2, Pc-2, and Pc, with nearly every amino acid found at P2 and Pc-2 [38Koch M. et al.Structures of an MHC class I molecule from B21 chickens illustrate promiscuous peptide binding.Immunity. 2007; 27: 885-899Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 57Chappell P. et al.Expression levels of MHC class I molecules are inversely correlated with promiscuity of peptide binding.Elife. 2015; 4e05345Crossref PubMed Scopus (83) Google Scholar]. Other chicken class I molecules, like BF2*02:01 and BF2*14:01, use broad binding pockets capable of accommodating many amino acids with hydrophobic side chains, which are particularly common in most proteins [57Chappell P. et al.Expression levels of MHC class I molecules are inversely correlated with promiscuity of peptide binding.Elife. 2015; 4e05345Crossref PubMed Scopus (83) Google Scholar]. The correlation of peptide repertoire with resistance to Marek's disease was unexpected. One hypothesis to explain this correlation [57Chappell P. et al.Expression levels of MHC class I molecules are inversely correlated with promiscuity of peptide binding.Elife. 2015; 4e05345Crossref PubMed Scopus (83) Google Scholar] is that the few MDV peptides pres