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Distinctive Polymorphism of Chicken B-FI (Major Histocompatibility Complex Class I) Molecules

Posted on: Wednesday, 5 May 2004, 06:00 CDT

ABSTRACT The major histocompatibility complex (MHC) in chickens influences disease resistance, but the mechanism is not understood. In Leghorn lines, the MHC contains 2 closely-linked class I loci, B- FI and B-FIV. Previously, we determined nucleotide sequences of wellexpressed class I (B-F) genes from unique MHC haplotypes of broiler chicken lines. More recently, we identified 7 new B-F [alpha]1[alpha]2-coding sequences from less well-expressed loci by amplification of genomic DNA from unique broiler haplotypes. Phylogenetic analysis of chicken MHC class I [alpha]1[alpha]2- coding sequences resolved 2 clusters (Groups A and B), which appear to correspond to B-FIV and B-FI loci, respectively. Compared with B- FIV locus, B-FI alleles were less polymorphic overall, but nevertheless demonstrated evidence of diversifying selection. The most striking feature of B-FI alleles is a conserved, locus- specific motif in the a helix of the [alpha]1 domain, a region that is highly variable in B-FIV alleles. This distinctive pattern of allelic polymorphism resembles that of the HLA-C class I locus in the human MHC (HLA). The conservation of the [alpha] helix of the [alpha]1 domain relates to HLA-C interaction with members of the killer immunoglobulin-like receptors on natural killer (NK) cells that are specific for recognition of HLA-C molecules and function to regulate activation of NK cells. Whereas HLA-C molecules may be dominant ligands for NK cell regulation, HLA-A and -B molecules are more important in presenting antigen to cytotoxic T lymphocytes. We hypothesize that chicken B-FI molecules may be specialized to serve similar functions as HLA-C molecules.

(Key words: class I, chicken, major histocompatibility complex, natural killer, polymorphism)

2004 Poultry Science 83:600-605

Abbreviation Key: CTL = cytotoxic T lymphocytes; HLA = human MHC; ILT = immunoglobulin-like transcript; KIR = killer immunoglobulin- like receptor; MD = Marek's disease; MDV = Marek's disease virus; NK = natural killer; TCR = T-cell receptor.

GENETIC RESISTANCE TO MAREK'S DISEASE IN CHICKENS

One of the most interesting features of the chicken MHC is the strong influence it exerts on resistance to infectious diseases (Bacon, 1987). MHC control of disease resistance has been especially well established for Marek's disease (MD) (Briles et al., 1983). MD is caused by a herpesvirus, and the final stage of the disease is characterized by the appearance of lymphoproliferative lesions (Calnek and Witter, 1997). Cell-mediated immune responses play an important role in genetic resistance to MD (Schat, 1991). Both natural killer (NK) cells (Sharma, 1981) and cytotoxic T lymphocytes (CTL) (Omar and Schat, 1996) have been proposed as key mediators of MD genetic resistance. The identity of the MHC gene or genes responsible for controlling resistance to MD is not known, but class I and II genes are strong candidates due to their known functions in immune responses. The following discussion will focus on potential roles of MHC class I proteins.

MHC Class I Genes and Proteins

Major histocompatibility complex class I molecules are expressed on the surfaces of virtually all cells of the body. The polymorphic class I heavy chain (encoded by a gene that maps to the MHC) is noncovalently associated with a nonpolymorphic light chain ([beta]- microglobulin) that is not MHC-linked. The class 1 heavy chain consists of [alpha]1, [alpha]2, and [alpha]3 domains on the outside of the cell, a transmembrane region, and a cytoplasmic tail. MHC class I molecules bind short peptides derived from intracellular proteins; the MHC I/peptide complex is recognized by T-cell receptors (TCR) on CD8+ T lymphocytes.

MHC in Humans

The human MHC (HLA) contains 3 classical class I loci, HLA-A, - B, and -C. The proteins encoded by the HLA-A, -E, and -C loci have a high degree of sequence similarity in comparisons made between loci as well as among alleles of a given locus. Nonetheless, important distinctions can be made between HLA-C molecules and HLA-A and - B molecules. HLA-A and -B allotypes are much more polymorphic than HLA- C, both in the number of amino acid residues that are variable and the average percentage of differences among allotypes in pair-wise comparisons (Zemmour and Parham, 1992). Most strikingly, the carboxyterminal half of the [alpha] helix in the [alpha]1 domain is very highly conserved among HLA-C molecules, and this region has some locus-specific residues. Cell surface expression of the HLA-C molecules is about one-tenth that of HLA-A and -B molecules (Snary et al., 1977).

MHC Class I Molecules Function to Present Antigenic Peptide to T Lymphocytes

In mammals, a crucial function of MHC class I molecules is to bind peptides derived from intracellular proteins and to present the bound peptides on the cell surface where they can be recognized by antigen-specific T lymphocytes. When a cell is infected with a virus or other intracellular pathogen, peptides from the pathogen are generated in the cytosol of the infected cells, and then transported to the cell surface in association with newly synthesized MHC class I molecules (reviewed in Germain and Margulies, 1993). A CTL with a receptor recognizing the MHC/antigenic peptide complex can then kill the infected cell, thereby preventing replication of the pathogen. The peptide-binding region of the class T molecule is created by pockets in the [alpha]1 and [alpha]2 domains of the heavy chain, which are highly polymorphic. In general, MHC class I molecules bind peptides that are 8 to 10 amino acids long. Usually, a given class I allele has rather broad specificity for peptides, but peptides bound by each allele have a "motif" that is characterized by a particular amino acid (or class of amino acids) at certain positions in the peptide. If a class I allele cannot bind any peptide derived from a given protein, no T-cell-dependent immune response can be made to that protein. HLA-A and HLA-B in humans are the dominant class I molecules for inducing CTL as part of the adaptive immune response (Littaua et al., 1991). Different HLA-C allotypes bind related peptides, as expected from the low polymorphism among HLA-C alleles (Falk et al., 1993). HLA-C molecules have been shown to be recognized by CTL induced in only a few viral infections (Littaua et al., 1991), perhaps related to the low expression and restricted peptide binding of HLA-C molecules (Neisig et al., 1998). On the other hand, HLA-C proteins may be more important ligands for receptors that regulate NK cells in the innate response (Guethlein et al., 2002).

MHC Class I Molecules Function as Inhibitory Ligands of NK Cells

The NK cells in mammals are part of the innate immune system, meaning that they are present in animals that have not previously been immunized and lack the exquisite specificity that is typical of the adaptive immune response represented by T cells and B cells. Another feature of NK cells is that their cytotoxicity is not MHC- restricted, unlike effector T lymphocytes. Mammalian NK cells kill a variety of tumor or virally-infected target cells. NK cells have been demonstrated to play important roles in resistance to several viruses, including cytomegalovirus (a herpesvirus) in mice (Scalzo et al., 1992). NK cell activity is regulated by both activating and inhibitory receptors, although the inhibitory receptors are better characterized and have higher avidity for their ligands (reviewed in Vilches and Parham, 2002). Negative signals from inhibitory receptors usually dominate over positive signals from activating receptors. A key discovery was that cell lines susceptible to NK killing generally had very low expression of MHC class I molecules on the cell surface (reviewed in Lanier, 1998). If the same cells were transfected to express certain MHC class I molecules at a high level, they became refractory to NK cell-mediated killing. These data demonstrated that NK cells recognized the presence of class I molecules on the surface of a potential target cell as a "turn-off" signal. Self-reactivity against normal cells is prevented because they express MHC class I molecules, which are ligands for inhibitory receptors on NK cells. Many viruses (including herpesviruses) down- regulate MHC class I molecules, presumably to avoid recognition by CTL. Loss of cell surface MHC class I molecules, however, releases NK cells to kill or to secrete interferon-[gamma] if their activating receptors have been engaged (Ljunggren and Karre, 1990). Viruses such as human immunodeficiency virus-1 (Cohen et al., 1999) selectively down-regulate HLA-A and -B, but not -C. The selective retention of HLA-C molecules on the surface of these virally- infected cells, which remain resistant to NK killing, indicates the importance of HLA-C molecules as ligands for NK inhibitory receptors. In a related strategy, many herpesvirsuses encode MHC class I-like molecules that function as decoys, interacting with NK negative regulatory receptors to evade killing of cells infected with virus (Chapman et al., 1999).

The NK inhibitory receptors recognizing MHC class I molecules belong to completely different gene families in mice and humans. In humans, a major family of NK regulatory receptors is the KIR (killer immunoglobulin-like receptor) family. Inhibitory receptors have long cytoplasmic domains containing on\e or more immunoreceptor tyrosine- based inhibitory motifs that mediate negative signals that antagonize positive signals from various activating receptors. KIR2DL (KIR with 2 immunoglobulin-like domains) interact with products of the human HLA-C locus, whereas distinct members of the KIR3DL (KIR with 3 immunoglobulin-like domains) family recognize a subset of HLA-B allotypes and at least one HLA-A allotype (Vilches and Parham, 2002). Dimorphic variation in residue 80 of the [alpha] helix of the [alpha]1 domain is found in HLA-C allotypes; KTR2DL have co-evolved to produce 2 KIR2DL types, one recognizing each of the 2 possible HLA-C position 80 allotypic groups. All HLA-C allotypes tested so far act as ligands for one of the 2 KIR2DL receptors; this is possible because the polymorphic HLA-C allotypes contain conserved regions within their variable [alpha]1 and [alpha]2 domains, and these conserved residues interact with the KIR2DL receptors. In the HLA-C [alpha]1 domain, the KIR contacts lie within the carboxyterminal portion of the [alpha]-helical region between residues 69 and 84; the [alpha]2 domain KIR contacts comprise residues within the amino-terminal end of the [alpha]- helical region (between residues 145 and 151).

Description of the Chicken MHC (B)

In chickens, the MHC is called the B complex. It was originally described as a system controlling blood group antigens (Briles et al., 1950). Haplotypes were defined serologically in experimental chicken lines by hemagglutination reactions and were numbered consecutively from B1 to B27 (Briles and Briles, 1982).

The chicken MHC from the B12 haplotype was recently sequenced in its entirety (Kaufman et al., 1999b). Overall, it is remarkably simple and compact. Only 19 genes map to the MHC region, which encompasses a length of 92 kb. [The HLA complex is about 20-fold larger.] It encodes 2 genes that are homologous to MHC class I genes in mammals (called B-F in chickens), and 2 genes that are similar to mammalian class II B-chain genes (termed B-LB in chickens). These genes are highly polymorphic. Two groups of scientists determined B- F sequences from standard haplotypes of Leghorn chickens. Sequences from one group were assigned to the B-FIV locus on the basis of their amplification in reverse transcription-PCR by primers derived from the 5' and 3' flanking regions of the BFIV*12 sequence and their relatively high expression (Hunt and Fulton, 1998). The second group (Kaufman et al., 1999a) also obtained B-F sequences from several standard Leghorn haplotypes and localized them to either the B-FI or B-FIV locus by long-distance PCR from adjacent genes. Some haplotypes (B14 and B15) apparently have only one intact B-F locus, B-FIV.

Structurally, the B-F molecule is predicted to resemble the mouse and human class I molecules, with most of the polymorphic residues predicted to contact either peptide antigen or TCR (Hunt and Fulton, 1998). B-FIV molecules were demonstrated to be highly effective in presenting antigen to MHC-restricted, antigen-specific CTL. Site- directed mutagenesis indicated that a residue critical for binding peptide in mammalian class I molecules was also important for peptide specificity of B-FIV molecules (Fulton et al., 1995). Sequence motifs of peptides bound to some class I allotypes (presumably the major expressed B-FIV molecule of each haplotype) have been described (Kaufman et al., 1995).

NK Cells in Chickens

Cells with functional characteristics of NK cells have been reported in chickens by several investigators (Sharma and Okazaki, 1981; Chai and Lillehoj, 1988; Myers and Schat, 1990). More recently, NK cells analogous to mammalian NK cells in antigenic phenotype have been described. They reside in embryonic spleen (but not adult spleen) and in the intestinal intraepithelial lymphocyte population of the adult gut (Gobel et al., 1994, 2001). These cells have a specific antigenic phenotype: CD8[alpha]-positive, CD8[beta]- negative, TCR-negative, and intracellular CD3-positive (Gobel et al., 1994, 2001). In addition, a monoclonal antibody specific for chicken NK cells, called 28-4, has been produced (Gobel et al., 2001).

Cells with NK activity have been implicated in resistance to MD in chickens. Chickens that are genetically resistant to MD have increased NK activity in spleen after challenge with virulent Marek's disease virus (MDV), whereas chickens that are genetically susceptible to MD exhibit reduced NK activity (Sharma, 1981). Also, cell surface B-F molecules are downregulated following infection of a cell with MDV (Hunt et al., 2001). Thus, MDV resembles mammalian herpesviruses in its ability to dramatically reduce cell surface expression of MHC class I proteins.

At present, there is no functional evidence in chickens or any other nonmammalian species for activating or inhibitory NK receptors that bind MHC class I molecules. However, 2 members of the paired immunoglobulin receptors, which belong to the larger super immunoglobulin family that includes KIR, have been reported in chickens (Dennis et al., 2000). Furthermore, in humans KIR are related and closely linked to immunoglobulin-like transcripts (ILT) genes. ILT in humans bind some HLA classical class I molecules with rather broad specificity and inhibit killing by NK and T cells (Colonna et al., 1997). Several transcripts and genomic sequences that are equally related to KIR and to ILT have been described recently in chickens; some of these chicken genes have 2 immunoglobulin-like domains and immunoreceptor tyrosine-based inhibitory motifs (Thomas Gobel, 2002, Avian Immunology Research Group meeting, personal communication). These are candidates for NK inhibitory receptor genes in chickens. Once thought to exist as a multigene family only in primates, several KIR have recently been reported in cattle (McQueen et al., 2002).

Molecular Characterization of the MHC (B) Complex in Commercial Broiler Chicken Lines

Until recently, virtually all molecular and functional studies of chicken MHC were conducted in Leghorn chickens. The Leghorn breed of chickens derives from a limited genetic pool and does not represent the diversity of the species as a whole (Simonsen et al., 1989). The avian immunogenetic program at Auburn University has the only pedigreed experimental chicken lines in existence that are segregating for well-characterized broiler MHC haplotypes, and also has the capability of typing MHC class I and class II alleles in these haplotypes. For molecular characterization, each distinct haplotype was obtained in the homozygous state in the F2 generation. By reverse transcription-PCR, we amplified the expressed B-F and B- LB genes in these broiler haplotypes. The amplicons were subsequently cloned and the nucleotide sequences were determined (Li et al., 1997, 1999; Livant et al., 2001). B-F/B-LB nucleotide sequence analysis of broiler MHC haplotypes revealed 7 new haplotypes with novel class I and class II alleles. Also, B-F sequences identical to standard haplotypes B2, B6, B13 (=B4), B15, and B21 were found in broilers. Recently, we obtained nucleotide sequences of less well-expressed B-F and B-LB genes in the 7 unique broiler haplotypes by amplification of genomic DNA; also, 2 additional novel haplotypes were identified in broilers by determining genomic B-F sequences of previously uncharacterized haplotypes (Livant et al., 2004).

Distinctive Polymorphism of B-FI Sequences

Phylogenetic analysis was performed on B-F sequences from broilers and published B-F sequences from Leghorns (Guillemot et al., 1988; Kaufman et al., 1992; Hunt and Fulton, 1998; Kaufman et al., 1999b). B-FI and B-FIV locus sequences from Leghorn standard haplotypes clustered in distinct groups (B and A, respectively) (Livant et al., 2004). Every unique broiler haplotype had one B-F sequence that clustered with Leghorn B-FIV sequences in Group A; if a haplotype had a second B-F sequence, it clustered with Leghorn B- FI12 (B-FI sequence from B12 haplotype) in Group B. These results are consistent with Groups A and B corresponding to products of distinct loci, and allowed us to tentatively assign our unique broiler B-F sequences to loci.

Of the 9 Group B (putative B-FI locus) alleles differing in [alpha]1[alpha]2 domains, 6 have been uniquely found in broiler lines. There are fewer B-Fi than B-FIV alleles, with several haplotypes sharing the same B-FI sequence ([alpha]1 and [alpha]2 coding domains), despite having unique B-FIV sequences. Furthermore, Group B sequences (which include all B-FI alleles) are unusual in that they have a highly-conserved, locus-specific motif in the carboxyterminal half of the [alpha]1 domain (from residues 71 to 82, Figure 1); in this region, B-FIV sequences are highly variable, with the exception of residues 71 and 82 which are also locus-specific and conserved in B-FIV molecules (Figure 1). Outside of this [alpha]- helical region (between residues 1 to 70 and 83 to 179 in the [alpha]1 and [alpha]2 domains) the polymorphisms are not specific to B-FI or B-FIV loci. This pattern suggests that interlocus recombination between B-FI or B-FIV loci has occurred outside the amino acid 71 to 82 region. The high degree of conservation of the amino acid 71 to 82 B-FI motif suggests selective pressure for its retention. The most likely functional constraints are either specificity for an important peptide, in that the [alpha]-helical region of the [alpha]1 domain has a dominant influence on the sequence of peptides bound (Barber et al., 1997), or interaction with another ligand such as a killer inhibitory or activating receptor. It is intriguing that residues 71 to 82 in the [alpha]1 helix of B-FI molecules correspond to the region of HLA-C with conserved, locus-specific residues contacting KIR (gray box in Figure 1). Also, residues 147 to 149 in the [alpha]2 helical region are invariant in B-FI but highly variable in B-FIV molecules; these residues over\lap the corresponding region in HLA-C [alpha]2 helix that provides the second set of contacts for KIR (Figure 1).

FIGURE 1. Amino acid sequence variability in B-FIV and B-FI molecules. Variability was determined by the method of Wu and Kabat (1970). A solid vertical line denotes a highly variable position (WuKabat index > 4.0), whereas a dotted vertical line indicates a variable position (Wu-Kabat index < 4.0). Amino acid residue numbering is shown only for highly variable residues. Locus- specific, conserved motif between amino acids 71 to 82 in B-F Group B (B-FI) allotypes is shown in enlargement, with consensus sequence on top and alternate amino acids below. Corresponding sequence in this region is also shown for B-FIV allotypes, which exhibit high diversity in this region. Figure is based on a total of 21 B-FIV and 9 B-FI sequences. "Contact residues for peptide (Saper et al., 1991); only residues that are variable in B-FIV or B-FI allotypes are labeled. T-cell receptor contacts ([Delta]); [alpha]-helical region (++).

Although phylogenetic analysis shows that chicken B-FI alleles are no more closely related to HLA-C than they are to HLA-A or -B alleles, the B-FI allotypes share some distinctive features with HLA- C molecules. B-FI allotypes are much less polymorphic than B-FIV, and the conservation of the carboxyterminal half of the a helix in the [alpha]1 domain is even more dramatic than that seen in HLA-C. Overall, the number of polymorphic amino acid positions in the [alpha]1 and [alpha]2 domains of B-FI and HLA-C molecules is very similar: 30 residues in HLA-C (Zemmour and Parham, 1992) and 32 in B- FI. This compares with 42 polymorphic positions in HLA-A, 43 in HLA- B, and 58 in B-FIV. More importantly, the pattern of sequence conservation in B-FI resembles that of HLA-C, both of which have overall low variability in the [alpha]1 and [alpha]2 domains. In contrast, HLA-A, HLA-B (Lawlor et al., 1990), and B-FIV (Figure 1) have high amino acid sequence variation, particularly in the a helix of the [alpha]1 domain. Despite the overall low sequence variation in HLA-C and B-FI, both molecules have a nonsynonymous-to- synonymous substitution ratio >1 in the 37 amino acid residues that contribute to the peptide binding site (Zemmour and Parham, 1992; Livant et al., 2004). Because a ratio > 1 is considered evidence of positive selection, these data indicate that HLA-C and B-FI genes have undergone past selection for diversification in their peptide- binding sites, presumably driven by pathogen pressure. Thus, one probable function of B-FI molecules is to present antigenic peptide to the cells of the immune system.

Furthermore, structural similarities between B-FI and HLA-C molecules suggest additional predictions. First, different B-FI allotypes are likely to bind peptides with similar sequence motifs because of the low polymorphism in the peptide-binding site. Because of the locus-specific, highly-conserved sequence in the a helix of the [alpha]1 domain, B-FI molecules should bind unusual peptides with a motif quite different than any B-FIV molecules. Finally, the unique conserved B-FI [alpha]1 sequence also may contain contact residues for another receptor (in addition to TCR), perhaps similar to KIR in humans.

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S. J. Ewald*[dagger],1 and E. J. Livant+

* Department of Pathobiology and [dagger] Department of Poultry Science, Auburn University, Auburn, Albania 36849-5519

2004 Poultry Science Association, Inc.

Received for publication August 1, 2003.

Accepted for publication November 25, 2003.

1 To whom correspondence should be addressed: ewaldsj@ vetmed.auburn.edn.

Copyright Poultry Science Association Apr 2004

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