Download Evolution of MHC class I genes in higher primates

Immunology and Cell Biology (1996) 74, 349-356
Evolution of MHC class I genes in higher primates
KRISTIN LIENERT and PETER PARHAM
Department ofStructural Biology. Stanford University School ofMedicine. Stanford, California. USA
Summary The classical major histocompatibility complex (MHC) class I genes are consen-'ed in higher
primates. Motifs common to human, chimpanzee and gorilla alleles indicate that class I alleles diverged from
ancestral sequences that existed before separation of these species. Analysis of native human populations such
as Australian Aborigines and Amerindians shows that HLA-B is characterized by rapid generation of new
alleles. HLA-A and -C appear to be evolving more slowly. Comparison of alleles for orthologous class I genes
in humans and other primates confirms that similar mechanisms contribute to the generation of new alleles in
these species.
Key words: Amerindian, Australian Aborigine, evolution. MHC class I, primate.
Introduction
The molecules of the major histocompatibility complex
(MHC) are an important component of the specific immune response. The class I and class II human leucocyte
antigen (HLA) molecules shape the Tcell repertoire by
positive and negative selection in the thymus. In the periphery, CD8 * and CD4 * T cells respond to foreign antigen only when presented in the context of a HLA class I
or class II molecule, respectively. The human MHC consists of the classical class I genes HLA-A, -B and -C, the
class II genes HLA-DR, -DQ and -DP, and a number of
non-classical genes and pseudogenes.
During the past 20 years, attention has primarily focused on the role of HLA antigens in transplantation
immunology and cell-mediated graft rejection. Transplant
donors and recipients are traditionally typed by serology
to assess the phenotypic match at the HLA-A, -B and -DR
loci. HLA-DQ can often be assigned on the basis of linkage disequilibrium with HLA-DR. HLA-DP cannot be
typed by conventional serological methods, but its effect
on solid-organ transplant rejection is minimal. HLA-C
has been effectively ignored, considered an enigma because of its low cell-surface expression' and weak stimulation of alloantisera.^-^ In addition to resultant advances
in clinical transplant matching, the classical class I genes
have been characterized in great detail, revealing distinctive traits for the HLA-A, -B and -C loci.
HLA-B appears to bc the major focus for diversification
and generation of new class I alleles. This locus has the
greatest number of alleles of all the class I genes, diverse
ethnic groups being characterized by a preponderance of
unique alleles compared to HLA-A. On the other hand,
HLA-A may be headed in the opposite direction, that of
evolutionary demise. The increasing number of HLA class
Correspondence: Dr Peter Parham, Department of Structural
Biology, Fairchild Building. Stanford University School of Medicine, Stanford. CA 94305-5400, USA.
Received 1 May 1996; accepted I May 1996.
*The MHC nomenclature derives from the taxonomic names
for the respective ape species: Pan troglodytes. Pan paniscus.
Gorilla gorilla, Pongo p^gmacus and H^lobates lar.
I 'blank' alleies characterized are of the HLA-A locus."' *,
and certain HLA-A alleles have poor affinity for CD8,
resulting m inefficient recognition and activation of cytotoxic T lymphocytes (CTL).^ The health of an individual
who has no functional HLA-A antigens lends support to
the theory that HLA-A is non-essential for presentation of
viral and endogenously derived foreign antigens.^ Recent
new research on the HLA class I molecules and natural
killer (NK) cells thrusts HLA-C into the limelight, and
reveals a primary role for HLA-C in NK cell regulation.^-^
NK cells, often considered to be an immunological relic,
carry receptors for epitopes on the a I domain of class I
HLA molecules. Interaction between the class I molecule
and the killer cell inhibitorv' receptor (KIR) results in
inhibition of NK cell cytolysis."^ KIR receptors for
HLA-B and -C have been identified, but none as yet for
HLA-A.
As more is learned of the role HLA class I molecules
play in immunity, it becomes of increasing interest to
understand how these molecules evolve and adapt to different tasks. Study of isolated human populations has
established that new class I alleles have evolved within the
time-span of modern human evolution. This indicates
that MHC class I loci have the ability to evolve rapidly
under selective pressure. However, the period of Homo
sapiens evolution is relatively short within the overall
span of mammalian evolution. Study of the MHC genes
of closely related primate species extends the time frame
over which MHC gene evolution can be assessed. Several
laboratories have concentrated on the characterization of
non-human primate MHC genes, and a sizeable data base
of cDNA sequences for orthologous class I and class II loci
established. This review will focus on the class I MHC
genes in higher primates, and in so doing demonstrate the
dynamism of the evolution of the class I genes and their
trans-species mode of evolution.
HLA class I in human populations
At the time of writing, 66 HLA-A alleles, 152 HLA-B
alleies and 33 HLA-C alleles have been defined (K Arnett
350
K Lienert and P Parhan
and S Marsh, pers. comm., 1996). The number of known
class I alleles continues to increase as DNA genotyping
defines subtypes of serological HLA specificities, and population studies are conducted on individuals of diverse
ethnic origin. Inherited polymorphisms in the MHC originate with point mutations in the germ line of individuals.
Sequence comparisons of class I alleles have established
that new alleles are most often generated by a process of
gene conversion. Typically, a segment from one allele is
introduced into a parental allele, thereby replacing that
segment and generating a unique recombinant allele. In
length, the converted segment can range from a few to 100
or more nucleotides in length. For some recombinants.
the parental alieles are uniquely defined, .whereas for
others there are alternative possibilities. It should be emphasized, however, that the original source of allelic polymorphism is point mutation, as recombination in the
absence of sequence difference has no diversifying eff'ect.
Population studies show that certain HLA genes are the
most polymorphic structural genes in the human genome.
Large urban populations are characterized by a 'flat' distribution by which many alleles are present at polymorphic frequency (>l%) and none is a "wild-type" allele.
However, due to increasing admixture and dilution of the
gene pool, such populations are somewhat artificial and
the effect of natural selection on the distribution of HLA
alleles is obscured. Studies of isolated native populations
such as the Amerindians and the Australian Aborigines,
in which the extent of admixture is minimal, may provide
a more accurate picture of the distribution of HLA alleles
as the result of natural selection. Analyses of the class I
alleles of both of these ethnic groups show a similar pattern of allelic distribution.
Native human populations
Serological studies of HLA antigens in Australian Aborigines showed a restricted number of HLA antigens.'''Hay et al.^^ analysed the class I antigens of two populations from the Northern Territory, designated 'Northern'
or 'Central' according to the location of their tribal
grounds. Four HLA-A antigens (A2, A24. Aw34 and All)
and five HLA-B antigens (B13- Bw56, Bw60, Bw61 and
Bw62) were found in the Northern population, with two
more identified in the Central population (B39 and B7).
Molecular analyses confirmed the serological results, Gao
et al. found a conservative distribution of HLA-A allctcs
encompassing one allele from each of the five HLA-A
scrologically cross-reacting groups (CREG) (X Gao.
ASEATTA scientific meeting. Adelaide. 1994). In this
way. HLA-A polymorphism is being used to maximum
advantage with a minimum number of alleles, Alleles with
the greatest variation in antigen-presenting repertoires are
retained, while alleles presenting similar arrays of peptides are not found. This maximizes the ability of hetcrozygotes in the population to present a wide variety of
foreign antigens.
The HLA-B locus also shows a paucity of variation in
Australian Aborigines. The most common HLA-B antigens were confirmed at the molecular level by Lienert et
al.^"* Two new HLA-B alleles have been identified, and
appear unique to Australian Aboriginal populations.''*'^
Both alleles are part of the large B15 allelic family. Many
ethnic groups carry a unique B15 allele that appears to
have evolved in the time since the origin of the population. Substitution within allotypes of the B15 family are
almost universally confined to the al and a2 domains
which form the antigen binding cleft, and thereby confer
functional polymorphism in peptide presentation to cytotoxic T cells.
Analysis of class I alleles of Amerindian populations by
Belich et al.^^ and Watkins el al,*'' found patterns of
polymorphism similar to those in the Australian Aborigines. Amerindian groups show limited HLA polymorphism, which probably reflects the small founder populations that colonized the Americas by overland migration
from Asia. The number of alleles identified at both the
HLA-A and -B loci was small, and previously undetected
heterogeneity was restricted largely to HLA-B. A combined total of nine new HLA-B alleles was identified in
three tribes of South American Indians, whereas only one
new variant at the HLA-A locus was identified.'^
Identification of new functional HLA-B alleles from
these isolated native populations suggests that diversification of class I loci can take place much more rapidly than
previously estimated. Australia has a history of human
occupation of at least 50 000 years.'^ Until at least
18 000 years ago. Australia was physically a part of SouthEast Asia. Australia and New Guinea were joined by a
land bridge across the present Torres Strait and Arafura
Sea regions, but were eventually separated with the rising
of the seas at the end of the last Ice Age.''^ The Amerindians entered the Americas by overland migration from
Asia via the Behring land bridge between 11 000 and
35 000 years ago.-" Limited HLA polymorphism in both
these populations probably reflects the small founder
populations that colonized these continents. However,
identihcation of new HLA alleles indicates considerable
diversification since separation. Consistent with a recent
evolution for these alleles are their simple structural relationships with pre-existing HLA-B alleles. which emphasizes intcrallelic recombination or conversion as the principal factor in HLA-B diversification. Selection of new
HLA variants could be the result of pressures encountered
upon entering a novel geographical environment. For
populations having small numbers of alleles and more
homozygotes. like Amerindian tribes and the Australian
Aborigines, the advantage of any new allele is believed to
be greater than in populations with many alleles. such as
modern Caucasian populations. Balancing selection could
then lead to rapid assimilation of the new allele into the
population. Therefore, analysis of isolated native populations may provide more accurate clues to the impact of
natural selection on HLA polymorphism.
Analysis of the class I alleles found in isolated native
populations may help define population relationships and
correlations with geographical, historical and linguistic
similarities. Analysis of HLA phenotypes in 30 ethnic
groups conducted as part of the Third Asia Oceania Histocompatibiiity Workshop confirmed the general concept
of four major groupings of the world's populations. A
Class I genes in primates
phylogenetic tree constructed from the HLA gene frequencies showed that Negroids branch first, followed by
groups of Australoids. with Caucasoids and Mongoloids
last."' Maintenance of the major HLA-A allelie lineages
during the migration of people from Africa was then demonstrated in a study by Madrigal et al.-- More recently,
two unique HLA alleles have been identified in African
Americans. The number of polymorphic substitutions,
and the complex relationships with other HLA-A and -B
alleles. indicates that these novel alleles are of ancient
origin.
Ancient class I alleles
HLA-A*800I
HLA-A antigens cluster into five groups (CREG). defined
by serological cross-reactions of antigens within each
group {Fig. 1). Molecular analysis confirms that antigens
grouped serologically are usually similar at the level of
nucleotide sequence.-^ Notable exceptions are the A30
alleles, which group with the A19 family by serology but
are closer in sequence to the A3 family.^'' HLA-A*8001
represents a sixth HLA-A family.^^-^^ This allele is char-
HLA-A-3901
A19 family
HLA-A-0201
A2 family
AlO family
•Gogo-AOlOl
-Gogo-A0201
HLA-A-2402
1
A9 family
A3 family
HLA-A'O3O1
HLA-A*aOO1
A80 family
Fig. I. A phylogenetic tree of selected primate A locus alleles
eonstructed using the UPGMA mclhod. The HLA-A alleles segregate into six families based on serological and nucleotide similarities. The six HLA-A families further cluster into iwo ancestral
lineages. Chimpanzee A locus alleles group in the A3/A9 ancestral lineage, whereas gorilla A loeus alleles group in the A2/AI0/
A19 ancestral lineage, A bovine class 1 MHC sequence. BI 3-6. is
the outlier for the analvsis.
351
acteristically HLA-A. but at positions which define
family-specific substitutions. A*800I has a motif that
does not correspond to the A2. A3. A9. AlO or A19
families. The A*8001 and A3 family motifs are identical
in the 5' half of the coding region, which includes exons 2
and 3 encoding the antigen recognition site; however, in
the 3' part of the coding region the A*8001 motif bears no
close relationship to the A3 family motif, and is similarly
divergent from all five family motifs. Although closest in
sequence to A*010 i. A*8001 diff"ers from that allele by 34
nucleotide substitutions, producing 24 amino acid replacements spread throughout the sequence. Four of the
substitutions within the a I and a2 domains are not
present in other HLA-A sequences, but three of them exist
in either HLA-A homologues of the great apes or in other
human class I loci.
Evolutionary trees show how the five HLA-A families
divide into two more ancient lineages, one comprising the
A2. AlO and Ai9 families and the other the A3 and A9
families (Fig. 1).-^-^ Characterization of HLA-A homoiogues in the great apes reveals gorilla Gogo-A alleles to be
of the first lineage, while chimpanzee Patr-A alleles are of
the second.-** Thus both lineages predate the separation of
humans, chimpanzees and gorillas, and were present in
the common ancestor of the three species. Parsimony
analyses indicate that the A*8OOI sequence represents a
sixth family of HLA-A alleles, one that is included in the
lineage with the A3 and A9 families. HLA-A*8OOI may be
an old allele of African origin that did not disseminate
from Africa during the first colonization of Europe and
Asia bv humans.
HL4-B*7301
Similarly. HLA-B73 may represent an ancient lineage of
HLA-B alleles. The B73 antigen is encoded by the allele
B*73OI. and was the last 'official' serological HLA-B type
to be defined at the molecular level.-^ As for HLAA*8001. the sequence of the B*73O1 allele docs not conform to the pattern defined by the previously studied
HLA-B alleles, and the features that distinguish B*7301
from other HLA-B alleles are concentrated in the 3' half
of the gene. At nine positions, B*73OI encodes a residue
found in no other HLA-B allele: however, eight of these
substitutions are present in other human and/or ape class
I genes. Parsimony analysis of cxons 4-8 of HLA-B illustrates the divergence of B*73O1 from other HLA-B alleles,
and indicates that B*73O1 is on a separate branch to all
other HLA-B alleles.
Previously, two lineages of chimpanzee and gorilla B
alleles had been defined on the basis of a polymorphism in
length of the transmembrane region.-** With determination of the primary structure of B*73O1. the same two
lineages are shown to be present in humans (Fig. 2). The
coding region of B*73O1 comprises 1092 nucleotides.
compared to 1089 nucleotides for other HLA-B alleles.
due to an unusual deletion-duplication event in the transmembrane region. Although not present in other HLA-B
alleles. this distinctive motif in cxon 5 is present in some
gorilla and chimpanzee B alleles. Thus, the two lineages of
352
HLA-B*7301
Gogo-B0201
Patr-BOl
Patr-B02
HLA-B*0702
Papa-BOl
Gogo-BOlOl
Hyla-BOl
Popy-BOl
Consensus
K Lienert and P Parhan
951
t-tg
t-tg
t-tg
*
*
*
*
*
*
CCTAGCAGTC
1000
--c--a-ctg
—c—a-ctg
--c--a-ctg
**
**
•**
**
**
**
ACTGTGGTCA
-g-tc
-g-tc
-g-tc
c
c
a
1
a
gat
TCGGAGCTGT GGTCGCTGCT GTGATGTGTA
Fig. 2. Partial nucleotide sequence from representative primate B locus alleles. Two lineages of B alleles are distinguished by a
distinctive motif in cxon 5, Both lineages are represented in human, chimpanzee and gorilla B alleles. Hyphens indicate identity with
consensus sequence; asterisks indicate gaps inserted to improve the alignment.
B alleles defined by the deletion-duplication event in exon
5 appear to have diverged at a time prior to the divergence
of the modern human, chimpanzee and gorilla species.
The MHC loci in higher primates
The HLA region spans four megabases on the short arm of
chromosome 6. with the class I genes occupying the tclomeric 2 Mbp. The classical class I genes have a characteristic structural organization. Exons 2, 3 and 4 encode the
three extracellular domains a l . a2 and a3. respectively.
The al and a2 domains form the antigen-binding cleft,
the site at which foreign peptides are bound and presented
to cytotoxic T cells. A large intron separates exons 1-3
from exons 4-8. encoding the a3 domain, the transmembrane domain and the cytoplasmic tail. This physical separation of the gene into a 5' and 3' cluster correlates with
the distribution of polymorphic variation within the gene.
Although polymorphic residues can be found throughout
the HLA class I heavy chain, highly polymorphic positions are largely clustered in the al and a2 domains.
Positions with high variation arc those involved in the
interaction between MHC. peptide and TCR,-^"^
HLA class I alleles exhibit A-ncss. B-ness and C-ness,
indicating that exchange of large segments of sequence
between the class I loci has not been a major contributor to
diversity. Some 62 locus-specific positions are concentrated in cxons 4-8 in the 3' half of the class I gene.-" In
contrast, when alleles of a single locus are compared,
much of the variation in exons 4-8 of HLA-A. -B and -C
sequences vanishes. Thus, most substitutions that distinguish alleles of a locus are confined to the 5' part of the
class I gene (exons 1-3), and are characterized by coding
substitutions generating functional differences in the
antigen-binding site. Such observations reveal that different patterns of variation have evolved in the 3' and 5'
regions and imply that distinctive mechanisms of mutation and/or forces of selection have been at work.
Comparisons of alleles for orthologous class I genes in
humans and other primates contirm that similar mechanisms contribute to the generation of new alleles in these
species. Interlocus gene conversion is rare, but more fre-
quent intralocus conversion has produced a characteristic
patchwork pattern of polymorphism. Motifs common to
human, chimpanzee, gorilla and orangutan class I genes
are seen, indicating that the evolution of MHC genes is a
continual process that transcends spcciation.^-^
Orthologucs of HLA-A and -B are found in many species of non-human primates, including the great apes
(chimpanzees, gorillas and orangutans) and old-world primates (gibbons and macaques). Gorillas, chimpanzees
and humans form a closely related cluster, and the relative
separation between the three species has been the subject
of much debate.'-^ The evidence available indicates an
earlier separation for the gorilla (7-10 million years), followed by later divergence of chimpanzees and humans
(approximately 5 million years).^''"^^
The first non-human primate MHC class I sequences
were determined by Lawlor et al.^~' and Mayer et al.^^ in
1988. No substitutions permitted chimpanzee alleles as a
group to be distinguished from human alleles, whereas
locus specificity was readily apparent, enabling the sequences to be classified as three A and four B locus alleles.
Sixteen Patr-A alleles. 23 Patr-B alleles and 12 Patr-C
alieles have now been defined and this generalization still
holds true. Certain HLA-A and HLA-B alleles are more
closely related to particular Patr-A and Patr-B alleles than
they are to other human A and B alleles. Similarly. 14
gorilla class I sequences were clearly recognizable asfiveA
locus alleles. four B locus alleles and five C locus alleles.-^
In total, these results indicate that the human, chimpanzee and gorilla alleles diverged from ancestral sequences
that existed before separation of the three species, and
that much of the contemporary nucleotide diversity in
HLA, Patr and Gogo class 1 genes had accumulated before
species divergence.
All Patr-A alleles belong to the HLA-A3/A9/A8O lineage (Fig. I), confirming that this allelic lineage originated
prior to the divergence of humans and chimpanzees. Sequence similarities between human and chimpanzee B
alleles are most striking in exon 2. coding for the al
domain of the peptide-binding cleft, there being less
between-species homology in the remamder of the gene.
Many unique substitutions found in chimpanzee B alleles
are shared with alleles of the HLA-A3/A9/A80 lineage.
Class I genes in primates
again attesting to the age of this lineage and suggesting a
limited role for interlocus recombination in the generation of diversity at the B locus. ^"^ The basis for differences
in selective pressure at A and B loci during their evolutionary history remains unknown, but one possibility is
that the two loci play distinctive roles with regard to the
peptidcs they present. Alleles at the A locus could be
associated with peptides derived from parasites that have
had a long association with the host species or, alternatively, with conserved peptides that are found in many
parasitic organisms. The B locus, on the other hand, may
be more frequently under selection to bind newly encountered peptide types.
The orangutan is believed to have diverged from the
human lineage 12-15 million years ago and represents the
Asian ape most closely related to humans.""^ To date, a
locus orthologous to HLA-C has been identified only in
chimpanzees and gorillas, and has not been found in the
Asian apes. As for HLA-C, analysis of C orthologues in
non-human primates lags behind that of A and B. Sequence comparisons show HLA-B and -C are more closely
related than either is to HLA-A. and that HLA-A and
HLA-C are the most divergent.^'•'"••*- Combined with the
physical proximity of the HLA-B and -C genes and the
relative distance of HLA-A, the sequence similarity
strongly argues that HLA-B and -C are the products of a
gene duplication, which occurred subsequent to events
separating HLA-A from the common ancestor of-B and
-C. Further investigation of the C locus will address the
question of the age of the ancestral C gene. Calculation of
mutation rates based on divergence times of closely related C alleles in the pygmy chimpanzee places the date of
the ancestral C locus gene well before the African ape/
Asian ape separation (S Cooper, pers. comm., 1996).
Chen el al.. in their analysis of gibbon MHC class I alleles
in which Hyla-A and -B alleles were identified, obtained
evidence for two additional class I molecules which could
correspond to orthologues of HLA-C."^^ An independent
duplication of HLA-B seems to have occurred in the orangutan, which may also represent the ancestral HLA-C
orthologue."*-^
The MHC in chimpanzees
The chimpanzee is the closest evolutionary neighbour to
humans, and represents an evolutionary distance from
humans of approximately 5 million years, Serological
cross-reactivities**'* and sequence similarities suggest that
human and primate class I molecules have similar functions. The two species of chimpanzee, the common chimpanzee (Pan troglodytes) and the pygmy chimpanzee, or
Bonobo (Pan pani.scus). live in geographically separate
habitats, and have an estimated divergence time approximately half that of the human/chimpanzee separation. ^^
Recent data from our laboratory demonstrate conservation of sequence and function in the MHC class I genes of
the two chimpanzee species, which have been evolving
separately for 2.3 million years. T cells specific for peptide
presentation by the common chimpanzee class I allcle
Patr-A04 recognize the same peptide presented by the
353
pygmy chimpanzee class I allele Papa-A06.'*^ There are
six amino acid differences between Patr-A04 and PapaA06. Two of these changes are located in the antigenbinding cleft, but are not sufficient to abrogate CTL recognition. Further highlighting the lifetime of MHC
polymorphisms beyond individual species is the first example of an identical class I allele shared between species.
The Patr-C09 allele from a common chimpanzee corresponds to the Papa-C03 allele from the pygmy chimpanzee (S Cooper, pers. comm., 1996). The sequence identity
encompasses the entire 1101 nucleotide coding region.
Six intronic substitutions distinguish Patr-C09 and PapaC03, mutations which have presumably been acquired
since separation of the two chimpanzee species.
In contrast to the conservation of chimpanzee C alleles,
Patr-B appears to be evolving rapidly in a familiar scenario to what we see at the B locus in human populations.
An unusual lineage of B alleles has been identified in the
common chimpanzee (S Cooper, pers. comm., 1996).
Like the unusual HLA-B*73O1 allele discussed above, the
Patr-B 1 7 alleles are characterized by distinctive polymorphisms that deviate significantly from the Patr-B allelcs
already sequenced. In contrast to HLA-B*73O1, which
appears to be the only member of the family, there are
three members of the new Patr-B 17 lineage. The number
of unique substitutions compared with other Patr-B alleles suggests that the new Patr-B I 7 alleles have diverged
over an extended period, implying that they were present
in the human/chimpanzee/gorilla common ancestor.
However, this distinctive MHC allelic family has no apparent representation in modern humans, and no orthologous members have yet been found in the other great
apes.
MHC class I-related genes
This review has focused on the evolutionary dynamics of
the classical class I MHC genes. The non-classical class I
genes, such as HLA-E, HLA-F and HLA-G, appear to
have unique specialized functions and tissue distribution,
and are relatively non-polymorphic.'*''"•**' However, they
are clearly related to the classical class 1 genes by sequence
similarity, and episodes of genetic interaction between
classical and non-classical class I genes have been
proposed.''''•^** Two gene families related to the MHC
class I genes have distinctive relationships with both class
I and class II MHC genes.
The MIC gene family
Recently, Bahram et al. identified what is believed to be a
second lineage of mammalian MHC class I genes.^' The
MIC (MHC class I chain-related genes) family is highly
divergent from all of the known MHC class I genes. Phylogcnctic trees suggest that MIC genes predate the separation of placental and marsupial mammals some 140 million years ago.^' Southern hybridization indicates that the
MIC gene family is present in primates (human, chimpanzee, orangutan, baboon, gibbon, marmoset and tamarin)
and some phylogenetically distant mammalian species
354
K Lienert and P Parhan
(goat, pig, cow, dog and hamster), but not the mouse.
The MICA gene is located near HLA-B. and is the first
of the five fatnily members to be fully characterized.
MICA encodes a polypeptide with three external domains
(al, a2 and a3), a putative transmembrane segment and
a carboxy-terminal cytoplasmic tail. The MICA gene
product is similarly related to human and mouse class I
chains, having 15-21 and 19-30% amino acid sequence
identity in the al and a2 domains, respectively, and 3236% identity in the a3 domain. A function has not yet
been assigned to the MICA gene product; however, conservation of the cysteine residues involved in disulfide
bond formation, along with a number of other residues
believed to be critical for the structure of class I molecules, has led to the suggestion that the MICA chain folds
similarly to class I chains, and may have the capacity to
associate with peptide ligands.
The CDl gene family
The CDl molecules are coded for by a family of five
non-polymorphic genes on human chromosome 1.^-* The
human CDl molecules fall into two groups, one comprising CDl A. B, C and E and the other comprising CDID.
The structural organization of the CDl genes is similar to
the organization of the MHC class I genes, although the
overall sequence homology is low. The greatest homology
is between the CD 1 a3 domain and the a3 domain of class
I, or the p2 domain of class II. Thus CDl is as similar to
class I as to class II.
Given the structural homology between MHC genes
and CDl genes, and the fact that CDl molecules are
expressed on professional antigen-presenting cells, an
antigen-presenting function for CDl was an attractive
idea. It has now been demonstrated convincingly that
CDIB molecules present antigen to Tcells.^"* Unlike the
nonamer peptides presented by MHC class I molecules,
the CD IB-restricted antigens are long-chain fatty acids
and lipoglycans found in the cell wall of mycobacteriaand
several related genera, such as nocardia. rhodococcus and
corynebactcria.^^^"^*' Presentation of fatty acids and lipoglycans by human CDIB, and hydrophobic peptides by
the mouse CDID orthologue." is consistent with the
hydrophobicity of the CDl al and a2 domains.
The origin of the CDl gene family is conjectural at
present. Since CDl a3, class I a3 and class II p2 are
similarly related to each other, it has been proposed that
they diverged at approximately the same time from a
common ancestral antigen-presenting gene. Subsequent
evolution must have been accompanied by a chromosome
translocation, segregating CDl from the MHC^^ CDl
genes in the rabbit confirm the existence of two classes
of CDl. one of which (CDID) is conserved in all mammalian species, while the other bas been deleted in
rodents.^''•'^^ Considerable sequence homology between
the rabbit and the human CDl genes also indicates a slow
rate of evolution. By including CDl as a non-protein
antigen-presenting class of molecules, the immune system
appears to have extended the potential repertoire of foreign antigens recognized by T cells beyond the realm of
those peptides thai can bind to MHC class I and II molecules. At present, nothing is known about the CDl family
in non-human primates.
Conclusion
The central role of the MHC class I and class II genes in
the immune response is well documented and universally
accepted. Endogenously derived foreign peptides. complexed with MHC class I molecules, present a novel antigenic surface to cytotoxic T lymphocytes, stimulating the
CTL to kill the invaded cell. Generation of a highly polymorphic antigen-presenting system ensures that the population as a whole is protected from universal elimination. Individuals within a species vary in their capacity to
present individual foreign antigens, and in that way
spread the risk for the entire population. The recent discovery of the HLA class I-directed killer-cell inhibitory
receptors has elevated the position of class I molecules in
the specific immune response to a pivotal role in cytotoxic
elimination of damaged or infected cells. The evolutionary immunogenetics of the NK receptor molecules is an
area currently under investigation. The relationship between HLA-C and NK cells is particularly intriguing,
given the previously perceived minor role of both in adaptive immunity.
Acknowledgements
Thanks to Dr Stewart Cooper for critical reading of the
manuscript and communication of unpublished results.
KL is the recipient of a Postdoctoral Fellowship from the
Transplantation Society of Australia and New Zealand.
References
1 Snary D. Bamstabic CJ. Bodmer WF. Crumpton MJ. Molecular structure of human histocompatibility antigens: the
HLA-C series. Eur. J. Immunol. \911\^: 580-5.
2 Hajck-Rosenmayr A, JungI L, Stammler M, Kimbauer M.
HLA-C "blank" alleles express class 1 gene products. Biochemical analysis of four different HLA-C "blank" polypeptides. Immunogeneiiis 1989; 30: 399-404.
3 Takiguchi M. Nishimura L Hayashi H. Karaki S, Kariyone
A. Kano K. The structure and expression of genes encoding
serologieally undetected HLA-C locus antigens. / Immunol.
1989; 143: 1372-8.
4 Balas A. Garcia-Sanchez F. Gomez-Reino F, Vicario JL.
HLA class 1 allele (HLA-A2) expression defect associated
with a mutation in its enhancer B inverted AT box in two
families. Hum Immunol. 1994; 4L 69-73.
5 Lardy NM, Biikas RM. van der Horst AR, van Twuyver E,
Bontrop RE. de Waal LP. Cis-aeting regulatory elements
abrogate allele-specific HLA class 1 gene expression in
healthy individuals. / Immunol. 1992; 148: 2572-7.
6 Ishlkawa Y. Tokunaga K. Tanaka H et al. HLA-A null allele
with a stop codon, HLA-A*O215N. identified in a homozygous state in a healthy adult. Immunogenetics 1995; 43: 1-5.
7 Salter RD. Norment AM. Chen BP et al. Polymorphism in
the a3 domain of HLA-A moleeules affects binding to CD8.
Nature 1989; 338: 345-7.
Class I ^cnes in primates
8 Colonna M, Samaridis J. Cloning of immunoglobulinsuperfamily members associated with HLA-C and HLA-B
recognition by human natural killer cells. Science 1995: 268:
405-8.
9 Wagtmann N. Biassoni R. Cantoni C et al. Molecular clones
of the p58 natural killer cell receptor reveal immunoglobulinrelated molecules with diversity in both the extra- and intracellular domains, hnmuniiy 1995: 2: 439-49,
10 Wagtmann N, Rajagopalan S, Winter CC, Peruzzi M, Long
EO. Killer cell inhibitory receptors specific for HLA-C and
HLA-B identified by direct binding and by functional transfer. Immunity 1995: 3: 801-9.
11 Hay J, Bennett G, Sheidon A, Pugsley D. Serologic study of
MHC antigens in Australian Aborigines. In: M Aizawa (ed.)
The Third Asian-Oceania Histocompaiibility H'orkshop Conference. Sapporo: Hokkaido University Press. 1986: 556-8.
12 Bennett G, Hay J, Hctzel P, Curiel L, Madin T. Vamey M.
Serologic study of class I antigens in Aboriginal Australians.
In: M Aizawa (ed.) The Third .Asian-Oceania Hislocompatibility Workshop Conference. Sapporo: Hokkaido University
Press, 1986: 559-61.
13 Hay J. Bennett G. Sheldon A. Hetzel P. Aboriginal Australians. In: M Aizawa (ed.) The Third .Asian-Oceania Histocompatibility Workshop Conference. Sapporo: Hokkaido University Press. 1986: 295-7.
14 Lienert K. MeCluskey J. Bennett G. Fowler C, Russ G. HLA
class I variation in Australian Aborigines: characterisation of
allele B'152l. Tissue .Antif^ens 1995; 45: 12-17.
15 Petersdorf EW, Hansen JA. A comprehensive approach for
typing the alleles of the HLA-B locus by automated sequencing. Tis.sue .4niif,'ens 1995:46: 73-85.
16 Belich MP. Madrigal JA, Hildebrand WH ci at. Unusual
HLA-B alleles in two tribes of Brazilian Indians. Nature
1992:357: 326-9.
17 Watkins DI, McAdam SN, Liu X et al. New recombinant
HLA-B alleles in a tribe of South American Amerindians
indicate rapid evolution of MHC class 1 loci. Nature 1992:
357: 329-33.
18 Roberts RG. Jones R, Smith MA. Thermoluminescence dating of a 50,000-year-old human occupation site in northern
Australia. Nature 1990: 345: 153-6,
19 Bellwuod PS. The Colonization of the Pacific: Some Current
Hypotheses. Oxford: Clarendon Press, 1989.
20 Cavalli-Sforza LL, Menozzi A, Piazza A. The history and
Geography of Human Genes. Princeton, New Jersey: Princeton University Press. 1994.
21 Wakisaka A, Hawkin S. Konoeda Y, Takada A. Aizawa M.
Anthropological study using HLA antigen frequencies as a
genetic marker. In: M Aizawa (cd.) The Third.isian-Oceania
Hislocompalibility Workshop Conference. Sapporo: Hokkaido University Press, 1986; 197-208.
22 Madrigal JA, Belich MP, Hildebrand WH cl al. Distinctive
HLA-A,B antigens of black populations formed by interalielic conversion. / Immunol. 1992; 149: 3411-15.
23 Madrigal JA. Hildebrand WH. Belich MP ei al. Structural
diversity in the HLA-A 10 family of alleles: correlations with
serology. Ti.ssue Antigens 1993; 41: 72-80.
24 Kato K, Trapani JA, Allopenna J. Duponi B, Yang SY.
Molecular analysis of the serologically defined HLA-Awl9
antigens: a genetically distinct family of HLA-A antigens
comprising A29, A31, A32, and Aw33, but probably not
A30../ Immunol 1989; 143: 3371-8.
25 Domena JD, Hildebrand WH. Bias WB, Parham P. A sixth
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
355
family of HLA-A alleles defined by HLA-A*8001. Tissue
Antigens 1993; 42: 156-9.
Wagner AG, Hughes AL, landoli ML era/. HLA-A*8001 is a
member of a newly discovered family of HLA-A alleles.
Tissue Antigens 1993: 42: 522-9.
Firgaira FA, Male DA. Morley AA, The ancestral HLA-A
lineage split is delineated by an intron 3 insertion/deletion
polymorphism. Immunagenetics 1994; 40: 445-8.
Lawlor DA. Warren E. Taylor P, Parham P. Gorilla class I
major histocompatibility complex alleles: comparison to human and chimpanzee class 1. / Exp. Med. 1991: 174: 1491 1509.
Parham P. Arnett KL, Adams EJ et al. The HLA-B73 antigen
hai a most unusual structure that defines a second lineage of
HLA-B alleles. Tissue Antigens 1994; 43: 302-1 3.
BJorkman PJ, Saper M,^. Samraoui B, Bennett WS.
Strommger JL, Wiley DC. The foreign antigen binding site
and Tcell recognition regions of class I histocompatibility
antigens. Saiure 1987; 329: 512-18.
Parham P, Lawlor DA, Lomcn CE. Ennis PD, Diversity and
diversification of HLA-A. B, C alleles. / Immunoi 1989;
142: 3937-50.
Klein J. Origin of major histocompatibility complex polymorphism: the trans-species hypothesis. Hum. Immunol.
1987: 19: 155-62.
Lewm R. DNA clock conflict continues. Science 1988; 241:
1756-8.
Diamond JM, DNA-based phylogenicsof the three chimpanzees. Nature 1988: 332: 685-6.
Miyamoto MM, Koop BF. Slightom JL, Goodman M. Tennant MR. Molecular systematics of higher primates: genealogical relations and classification. Proc. Natl Acad. Sci. USA
1988:85: 7627-31.
Horai S, Hayasaka K, Kondo R, Tsugane K, Takahata N.
Recent African origin of modem humans revealed by complete sequences of hominoid mitochondrial DNAs. Proc.
Nail.icad. Sa. LSA 1995; 92: 532-6.
Lawlor DA. Ward FE. Ennis PD, Jackson AP, Parham P.
HLA-A and B polymorphisms predate the di\crgence of
humans and chimpanzees. Nature 1988; 335: 268-71.
Mayer WE, Jonker M. Klein D. Ivanyi P, Seventer G, Klein
J. Nucleotide sequences of chimpanzee MHC class I alleles:
evidence for /r^i/j.v-species mode of evolution. E.\tBO J..
1988:7: 2765-74.
McAdam SN, Boyson JE. Liu X et ul. A uniquely high level
of recombination at the HLA-B locus, Proc \ail .Acad. Sci.
USA 1994:91: 5893-7,
Andrews P. Cronin JE. The relationships ofSnapithecus and
Ramapilhi'cus and the evolulion of the orang-utan. Sature
1982; 297: 541-6.
Cereb N. Yang SY. The regulatory complex of HLA class I
promoters exhibits locus-specific conservation with limited
allelic variation,./. Immunol. 1994; 152: 3873-83.
Parham P. Lomen CE. Lawlor DA et al. Nature of polymorphism in HLA-A. -B. and -C molecules. Proc. Natl .Acad. Sei.
i'.SA 1988:85:4005-9.
Chen ZW, McAdam SN, Hughes AL, Dogon AL, Letvin NL.
Watkins DI, Molecular cloning of orangutan and gibbon
MHC Class I cDNA. The HLA-A and -B loci diverged over
30 million years ago, / Immunol 1992: 148: 2547-54.
Brodsky FM, Parham P. Evolution of HLA antigenic determinants: species cross-reactions of monoclonal antibodies,
Immunogcnetus 1982; 15: 151-66.
Cooper S. Kowalski H, Erickson AL et al. The presentation
356
46
47
48
49
50
51
52
K Lienert and P Parhan
of a hepatitis C viral peptide by distinct MHC class I allotypes from two chimpanzee species. / Exp. Med. 1996; 183:
663-8.
Geraghty DE, Wei X. Orr HT, Koller BH. Human leukocyte
antigen F (HLA-F). / Exp. Med. 1990; 171: 1-18.
Koller BH, Geraghty DE, Shimizu Y. DeMars R, Orr HT.
HLA-E. A novel HLA class 1 gene expressed in resting T
lymphocytes./ Immunol. 1988: 141: 897-904.
Geraghty DE, Koller BH. Orr HT. A human major histoeompatibility complex class I gene that encodes a protein with a
shortened cytoplasmic sequenee. Proc. Natl .Acad. Sci. VSA
1987:84: 9145-9.
Watkins DI, Chen ZW, Garber TL, Hughes AL, Utvin NL.
Segmental exchange between MHC class 1 genes in a higher
primate: recombination in the gorilla between the ancestor of
a human non-functional gene and an A locus gene. Immunogenetics 1991; 34: 185-91.
Watkins DI, Chen ZW, Hughes AL, Evans MG, Tedder TF,
Letvin NL. Evolution of the MHC class I genes of a New
World primate from ancestral homologues of human nonctassical genes. Nature 1990; 346: 60-3.
Bahram S, Bresnahan M. Geraghty DE, Spies T, A seeond
lineage of mammalian major histocompatibility complex
class I genes. Proc. Natl Acad. Sci. USA 1994; 91: 6259-63.
Klein J, O'Huigin C. The conundrum of nonclassical major
53
54
55
56
57
58
59
60
histocompatibility complex genes. Proc. Natl Acad. Sci. USA
1994; 91: 6251-2.
Martin LH, Calabi F, Milstein C Isolation of CDl genes: A
family of major histocompatibility complex-related differentiation antigens./'w. A^a^/.-fc^^ty, 5d. USA 1986:83:9154-8.
Porcelli S, Morita CT, Brenner MB. CDlb restricts the response of human CD4-8- T lymphocytes to a microbial antigen. Nature \992: 360: 593-7.
Beckman EM, Porcelli SA, Morita CT, Behar SM, Furlong
ST. Brenner MB. Recognition of a lipid antigen by CDlrestricted ap + T eells. Nature 1994; 372: 691 -4.
Sieling PA, Chatterjee D, Porcelli SA et al. CD I-restricted
T cell recognition of microbial iipoglyean antigens. Science
1995:269: 227-30.
Castano AR. Tangri S. Miller JEW et al. Peptide binding and
presentation by mouse CDl. Science 1995: 269: 223-6.
Calabi F, Bradbury A. The CDl system. Tissue Antigens
1991:37: 1-9.
Calabi F. Belt KT, Yu CY, Bradbury A, Mandy WJ, Milstein
C. The rabbit CDl and the evolutionary conservation of the
CDl family. Immunogcnetics 1989: 30: 370-7.
Ichimiya S, Kikuchi K, Matsuura A. Structural analysis of
the rat homologue of CDl. Evidence for evolutionary conservation of the CD 1D class and widespread transcription by
rat cells. / Immunol. 1994; 153: 1112-23.