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Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Facultad de Ciencias, Madrid, Spain
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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HLA-B27 is strongly associated with ankylosing spondylitis (AS)3 (1, 2) and reactive arthritis (3), and there is strong evidence that it is directly involved in the pathogenesis of these diseases (4). A number of HLA-B27 subtypes (B*2701–B*2715) have been identified, which differ among each other by one or few amino acid residues. These changes are mainly located in the peptide-binding site of the molecule and affect peptide specificity and T cell recognition. B*2705, which is widespread in human populations, B*2702, which is restricted to Caucasians, B*2704, which is restricted to and frequent in Orientals, and B*2707, found in India and Southeast Asia, are associated to AS (5). Three independent studies (6, 7, 8) have reported lack of association of B*2706 to AS, a subtype found mainly in Southeast Asia, in the same populations in which B*2705 or B*2704 was associated to this disease. A few B*2706 AS patients were reported from China, where this subtype is found at very low frequency (5), suggesting that lack of association of B*2706 with AS is not absolute and might be modulated to some extent by genetic or environmental factors. B*2709 is relatively frequent in Sardinia. In one study conducted in the Sardinian population, B*2709 was found in 10 of 40 healthy HLA-B27-positive individuals and in none of 36 HLA-B27+ AS patients (9). This study strongly suggested that B*2709 is not or is more weakly associated to AS than other B27 subtypes in this population. Recently, a B*2709 individual with sacroiliitis and oligoarthritis was found in continental Italy, where B*2709 is present at very low frequency (50), suggesting that, as for B*2706, lack of association of B*2709 with AS is not absolute.
Among the various hypotheses to explain the mechanism of HLA-B27 association to disease, one proposes that HLA-B27 is the restriction element for an "arthritogenic" peptide that would be the target Ag of CTL activated on external challenge, such as a bacterial infection (10). CTL-mediated damage in relevant tissues would be a primary pathogenic event that, together with additional processes susceptible to modulation by additional genetic factors, would finally lead to disease. The arthritogenic peptide model has not been proved and is only suggested by circumstantial evidence, and other pathogenetic mechanisms remain open (reviewed in 4). However, in contrast to other hypotheses, this one does not invoke unknown features for HLA-B27, other than its normal Ag-presenting function. In addition, recent findings in transgenic rats indicate that a major alteration of the HLA-B27-bound peptide repertoire prevents arthritis in these animals (11). According to this model, any disease-associated subtypes should be able to present the arthritogenic peptide(s) to CTL but B*2706 and B*2709 would be unable or less capable to do so. Thus, the peptide binding and antigenic differences between subtypes differentially associated to AS may be relevant to our understanding of the relationship between HLA-B27 and spondyloarthropathy.
Much of the polymorphism among HLA-B27 subtypes is clustered in the C/F pocket and determines the specificity for C-terminal peptide residues (12). Multiple studies have analyzed subtype-bound peptide repertoires (13, 14, 15, 16, 17, 18, 19, 20, 21), but the capacity of CTL to recognize a given peptide when presented by different subtypes has not been analyzed in depth. Few viral peptides are known to be recognized by the same T cells in the context of different subtypes (22, 23, 24, 25), and in only one case was cross-reactivity of an alloreactive CTL clone with various B27 subtypes shown to be mediated by recognition of the same peptide (26). However, allospecific T cell epitopes shared between B*2705 and other subtypes are not rare, suggesting that HLA-B27 subtypes behave synonymously in presentation of multiple peptides to CTL. Of the subtypes tested in a previous study (B*2701 to B*2706), B*2703 showed the highest cross-reaction with B*2705, with about 50% of anti-B*2705 CTL clones recognizing B*2703 (27).
The aim of our study was to assess T cell epitope sharing between B*2705 and B*2709, because they differ only by the D116H substitution (28) but are differentially associated with AS in one population (9). Differences in the recognition of a viral peptide in the context of both subtypes by at least a B*2709-restricted T cell line have been reported (29), but our goal was to determine whether such differences are common among T cells recognizing these two subtypes. Thus, we analyzed the degree of clonal cross-reaction between B*2705 and B*2709 in alloreactive responses. Because allospecific CTL recognize class I-bound peptides, the cross-reaction between B*2705 and B*2709 is an indication of the capacity of these subtypes to interchangeably present peptides to CTL.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The human class I-deficient HMy2.C1R (C1R) cell line and their transfectants expressing B*2705 and the mutant D116Y have been previously described (30, 31). Full length cDNA encoding B*2709 (28) (a kind gift of Dr. Rosa Sorrentino, University of L’Aquila, Italy) cloned into RSV5neo expression vector was transfected into C1R cells as previously described (30). In addition, genomic B*2709 DNA was obtained by site-directed mutagenesis of the B*2705 gene, cloned into the pUC18 vector and equally transfected into C1R cells. T2, a TAP-deficient human cell line, transfected with B*2705 was a gift of Dr. David Yu (University of California, Los Angeles, CA). When incubated at 26°C, this cell line expresses class I molecules presumably devoid of peptides. All these cells were cultured in DMEM supplemented with 5% heat-inactivated FCS (both from Life Technologies Laboratories, Paisley, U.K.). The expression levels of HLA-B27 on C1R transfectants were very high and identical for B*2705 and B*2709 (cDNA) and somewhat higher (166%) for the genomic B*2709 transfectant. They were tested by flow cytometry with the mAb ME1 (IgG1 specific for HLA-B27, -B7 and -B22) (32), as previously described (33).
T cell clones
Three sets of alloreactive CTL clones were used. A first set
(Table I
) consisted of CTL generated against B*2705 from three
unrelated donors: DL (HLA-A29, 31; B39, 44; DR2, 7); GM (HLA-A1, 24;
B7, 8; DR1, 3); and SR (HLA-A3, 29; B7, 44; DR2, 7). A second set
(Table II) consisted of CTL generated against B*2703 from donors DL and
GM, but cross-reactive with B*2705. The generation, culture conditions,
and fine specificity of both sets of CTL have been previously described
(27). A third set consisted of CTL clones generated
against B*2709 as follows. About 106 PBMC from
healthy HLA-B27-negative donor MM (HLA-A3, 11; B7; DR2, 7) were
stimulated with 105 irradiated (80 Gy) allogeneic
HLA-B*2709-positive lymphoblastoid cell line (LCL) Ci (HLA-A2, 10; B16,
27) and 106 irradiated (50 Gy) autologous PBMC in
Iscove’s modified DMEM with Glutamax (Life Technologies Laboratories,
Paisley, U.K.) supplemented with human AB sera (15%), gentamicin (50
mg/ml), streptomycin (0.1 mg/ml), and penicillin (100 U/ml). At weekly
intervals, MLR cultures were washed and counted, and 3 x
105 cells were seeded in a 24-well plate and
restimulated with the same mixture of feeder cells and stimulator LCL
as before in the presence of 20 U/ml rIL-2 (Hoffman LaRoche, Palo Alto,
CA). Clones were obtained by limiting dilution. Cells were seeded in
96-well plates containing the same irradiated autologous PBMC:B*2709
LCL ratio as in the MLR. Positive wells were considered clones when
they grew at dilutions below the limit of clonality determined by
Poisson statistical analysis. Statistical clones were screened for
HLA-B27 reactivity using B*2709-C1R target cells. Their specificity was
confirmed by testing the capacity of the ME1 mAb to inhibit lysis of
these target cells and their failure to kill untransfected C1R cells.
The 64.8P CTL clone, used as control (Table III), has been previously
described (31, 34).
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A standard 4-h 51Cr release assay was conducted as previously described (35), with minor modifications. For T2 transfectants, the same assay was used, but the cells were incubated for 18–24 h at 26°C before using them as target cells.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A total of 10 anti-B*2705 CTL clones (Table I
) from three unrelated donors (DL, GM
and SR) and 10 anti-B*2703 CTL clones (Table II) from DL and GM were tested for
recognition of B*2709. The fine specificity of these CTL with other
HLA-B27 subtypes (B*2701-B*2706) and mutants was previously
established. Based on the diverse reaction patterns with B*2701-B*2706
(Tables I and II), the anti-B*2705 and anti-B*2703 CTL used in
this study are a fair sample of the clonotypic diversity observed in
these alloreactive responses (27). All these CTL clones
were peptide dependent, as demonstrated by their failure to lyse the
T2-B*2705 transfectant cell line (Table III). The natural peptide epitope has
recently been reported (26) for one of these clones (CTL
27S69). In addition, distinct HPLC fractions from the B*2705-bound
peptide pool sensitized B*2705-T2 targets for lysis by CTL 20.8GRK,
37GRK, 33S69, and 36DLH (our unpublished observations).
Most anti-B*2705 CTL recognize B*2709
The alloreactive CTL clones raised against B*2705 were examined
for their ability to lyse C1R transfectant targets expressing B*2709
(Table I). All clones lysed B*2705-C1R targets and failed to lyse or
lysed marginally (CTL, 20.8GRK and 12.8DM5) C1R cells transfected only
with pSV2neo.
Of the 10 CTL clones analyzed, 8 cross-reacted with B*2709; 6 of them reacted equally with B*2705 and B*2709, and 2 (37GRK and 33S69) recognized B*2709 less efficiently (50% or less relative lysis). These results demonstrate that a large majority (80%) of the epitopes recognized by anti-B*2705 CTL are also present in B*2709, and they indicate that B*2709 is the antigenically closest subtype to B*2705.
High cross-reaction of anti-B*2703 CTL with B*2709
In a previous study (27), we showed that most (78%)
anti-B*2703 CTL clones cross-reacted with B*2705, whereas <20% of
these clones cross-reacted with any of the B*2701, B*2702, B*2704, or
B*2706 subtypes. Now 10 of the anti-B*2703 CTL cross-reactive with
B*2705 from donors DL and GM were tested for recognition of B*2709 on
C1R cells (Table II). Five clones failed to lyse B*2709 target cells.
Of those cross-reacting with this subtype, three (42GCP, 98DCJ, and
81DCJ) recognized equally B*2705 and B*2709, and two (63GLM and 62GCP)
lysed more efficiently B*2705 than B*2709 targets. These results
indicate that 50% of the B*2703 epitopes shared with B*2705 are
maintained in B*2709. Thus, B*2709 is antigenically closer to B*2703
than other subtypes except B*2705.
Differences among individuals in the reactivity of anti-B*2705 and anti-B*2703 CTL with B*2709
Although the number of CTL clones tested from each individual was
small, a clear difference in cross-reactivity with B*2709 was observed
among donors (Table IV). Only 2 of 7 CTL
clones from DL (29%) recognized B*2709, whereas 8 of 10 clones from GM
(80%), and the 3 clones from SR cross-reacted with this subtype. This
difference was due mainly to the anti-B*2705 CTL; none of the two
anti-B*2705 clones from DL and all those from GM (5 clones) or SR
(3 clones) recognized B*2709. In contrast, the fraction of
anti-B*2703 CTL clones from DL (2 of 5) or GM (3 of 5)
cross-reacting with B*2709 was similar.
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Distinct effects of natural mutations at position 116 on HLA-B27 allorecognition
Three different residues are found at position 116 among HLA-B27
subtypes: aspartic acid in B*2705, B*2703, and various other subtypes;
tyrosine in B*2706, B*2707, and B*2711; and histidine in B*2709. In a
previous report from our laboratory (36), the
Tyr116 mutation abrogated recognition by 54% of
anti-B*2705 and 53% of anti-B*2703 CTL clones. This mutant was
not or marginally recognized (lysis relative to B*2705 <30%) by 12 of
19 (63%) CTL clones used in our current study (Table V). In contrast, only 7 of the 20
anti-B*2705 plus anti-B*2703 clones (35%) failed to
cross-react with B*2709 (His116). This result
indicates that the H116 change has an smaller effect on allorecognition
than Tyr116.
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). All clones not
recognizing B*2709 also failed to recognize
Tyr116 (reaction pattern I). This group
represented 37% of the CTL clones tested. Those CTL cross-reacting
with B*2709 (64%) showed different reaction patterns. Two clones were
partially affected by His116 and failed to
recognize Tyr116 (reaction pattern II). Three
clones were unaffected by His116 but did not or
marginally recognized Tyr116 (reaction pattern
III). One clone was partially affected by Tyr116
and not by His116 (reaction pattern IV) and two
clones showed the reverse situation (reaction pattern V). Finally, 4
CTL clones were not affected by either change (reaction pattern VI).
Thus, the two mutations exhibited differential effects on 8 (42%) of
19 CTL clones compared (reaction patterns II–V). In 6 of these 8
clones (reaction patterns II–IV) the effect of
Tyr116 on CTL recognition was more drastic than
for H116. Taken together, these results indicate that the two natural mutations occurring at position 116 among subtypes have distinct effects on the antigenic properties of HLA-B27, and that D116Y is more disruptive than D116H.
High cross-reaction of anti-B*2709 CTL with B*2705
Ten statistical clones raised from an HLA-B27-negative donor
against B*2709 were tested for recognition of B*2705 (Table VI). Nine of the clones (90%) lysed
B*2705-C1R transfectant cells, 8 of them with an efficiency comparable
with but somewhat higher than the lysis of B*2709 targets and 1 (CTL
2B212) with decreased efficiency (38% relative lysis). Only 1 of the
10 clones tested failed to recognize B*2705. These results indicate
that a large majority, but not all, of the allospecific epitopes of
B*2709 are also present in B*2705.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The overwhelming majority of allospecific CTL, including those in this study are peptide dependent, and it is likely that CTL cross-reaction between subtypes generally reflects recognition of the same peptide in the different contexts (26). Thus, our results strongly suggest that many of the peptides that are relevant for allospecific T cell recognition are presented by both B*2705 and B*2709 to CTL.
The D116H change between B*2709 and B*2705 influences the nature of the
C-terminal (P
) amino acid side chain of bound peptides
(20). Whereas B*2705 binds in vivo peptides with basic,
aliphatic, and aromatic P residues (38), known
B*2709-bound peptides have only nonpolar aliphatic (L, V, I, M) and
aromatic (F) P residues (20). This is probably due to
loss of the Asp116 charge and to the larger size
of His116, which would hinder acceptance of very
bulky P side chains. This means a significant restriction in the
B*2709-bound peptide repertoire, relative to B*2705. In a recent
compilation of natural B*2705 ligands, 27 of 46 self peptides (59%)
showed basic or Tyr C-terminal residues, not reported among B*2709
ligands, and only 41% of the B*2705 ligands showed C-terminal motifs
common to those of B*2709 (39). The disparity between the
apparent degree of peptide sharing and the higher degree of CTL
cross-reaction has three possible explanations. 1) many cross-reactive
CTL would recognize different peptides in the context of B*2705 and
B*2709. This type of cross-reaction, although observed between
structurally distant class I allotypes (40, 41, 42), might be
less frequent for closely related subtypes and was not the case for the
only CTL clone in this study for which the peptide epitope is known
(Ref. 26 and our unpublished observations). 2) Ligands with nonpolar
P residues would be more immunogenic than those with C-terminal
basic or tyrosine residues. This is also unlikely because
B*2705-restricted viral epitopes have both aliphatic and basic P
residues (13, 22, 43, 44, 45, 46). 3) B*2709 could present ligands
with basic and/or Tyr P residues in low amounts, detectable by CTL
but not easily by biochemical methods. In support of this possibility,
a B*2705 ligand with C-terminal tyrosine (RRFFPYYVY) (26)
was found in much smaller amounts in the B*2709-bound peptide pool (our
unpublished observations). Thus, a comparison of peptide motifs is
insufficient to define the functional and antigenic similarity of
structurally close class I proteins.
The lower cross-reactivity of anti-B*2703 CTL with B*2709, relative
to anti-B*2705 CTL, can be explained by two related reasons. First,
B*2703 probably binds and presents to CTL mainly a subset of the
B*2705-bound peptides (27, 36) consisting of those with
the canonic B*2705 motifs at P2 and P, plus a basic P1 residue
(16, 17). Because B*2709 has a more restricted P motif
than B*2705, it probably shares less natural ligands with B*2703 than
with B*2705. In addition, the added effect of the two changes between
B*2703 and B*2709 (H59Y and D116H) on the conformation of some peptide
epitopes might be larger than the single H59Y change between B*2703 and
B*2705.
It is interesting that whereas the D116H change occurs alone in B*2709, the more disruptive D116Y change always occurs together with additional changes in HLA-B27 subtypes. At least in some cases, these additional changes, such as Y114D in B*2706, have compensatory effects on allorecognition (36). The significance of this observation is unclear, but it is compatible with the idea that HLA-B27 has evolved to diversify the structure of the C/F pocket, but avoiding too large disruptive effects at position 116, a critical one for this pocket. This would have been achieved either by introducing a single mutation with relatively moderate effects, as in B*2709, or by introducing additional compensatory changes.
Although, obviously, alloreactive CTL are not related to B27-mediated spondyloarthropathy, the findings in this study might be relevant to the understanding of the reported differential association of B*2705 and B*2709 to AS (9). They suggest that both subtypes may interchangeably act as restriction elements for many peptides. If the pathogenetic role of HLA-B27 is related to its normal Ag-presenting function (10), one would expect that those subtypes associated to AS, such as B*2705, B*2702, or B*2704, are able to present the relevant peptide(s), whereas subtypes apparently not or less associated to this disease, such as B*2709, are not. However, there is no correlation between the Ag-presenting similarities among B27 subtypes, as assessed with allospecific CTL, and their reported association to AS. For instance, whereas 80% of our anti-B*2705 CTL cross-react with B*2709, only 12% cross-react with B*2704 (27). The fact that B*2709 has lost a relatively small amount of B*2705-allospecific T cell epitopes considerably narrows down the number of B27-bound peptides, that are antigenic in the B*2705 but not in the B*2709 context. Presumably, an "arthritogenic" peptide might have this feature. Therefore, our results open the way to further characterization of peptides putatively involved in HLA-B27-mediated disease, focusing on a limited fraction of the B*2705-bound repertoire.
The relevance of our results to the understanding of the pathogenic role of HLA-B27 obviously depends on the strength of the evidence supporting that B*2709 is more weakly associated to AS than B*2705. Therefore, this issue deserves to be discussed here.
Because B*2709 has been found with a frequency high enough for statistical analysis only in Sardinia, the idea of its differential association to AS is based on findings in this population (9), described in the Introduction. In contrast to B*2706, in which an initial study reporting lack of association of this subtype in Thailand (6) was subsequently confirmed in two additional populations of Southeast Asia (7, 8), no statistical studies in other populations have thus far been possible for B*2709. With this limitation in mind, we must nevertheless point out that the critical point in the Sardinian study, as well as in those dealing with B*2706, is not only the absence of B*2709+ patients, but the fact that other HLA-B27 subtypes are normally associated to AS in the same population. This makes it unlikely that population-specific genetic or environmental factors account for the observed differential association, because such factors would have to act differently on individuals carrying different subtypes in the same population. In addition, although populations differ among each other genetically, environmental factors influencing HLA-B27-associated disease are probably ubiquitous (47). The situation with B*2709 and B*2706 is totally different from the reported lack of association of B*2703 with AS in West Africa (48); unknown genetic factors seem to protect from AS both B*2703 and B*2705 individuals in this population, where AS is extremely rare regardless of the subtype (49).
The occasional B*2709 or B*2706 individuals with AS reported from populations where these subtypes are in very low frequency indicates that lack of association with AS is not absolute. However, this is not in conflict with differential subtype associations established by statistical analysis within a population. It is well known that a low percentage of HLA-B27 negative individuals also develop AS. In conclusion, although the negative association of B*2709 with AS should be confirmed in other populations, the findings in the only population where it is found with significant frequency are not easily explained by genetic or environmental factors alien to HLA-B27 itself.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. José A. López de Castro, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Facultad de Ciencias, Cantoblanco, 28049 Madrid, Spain. E-mail address:
3 Abbreviations used in this paper: C1R, Hmy2.C1R; AS, ankylosing spondylitis; P, C-terminal peptide position; LCL, lymphoblastoid cell line.
Received for publication March 29, 1999. Accepted for publication June 7, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T cell clone. J. Immunol. 153:3093.[Abstract]
His116, differentiating the ankylosing spondylitis-associated HLA-B*2705 from the non-associated HLA-B*2709 subtype, influences peptide-specific CD8 T cell recognition. Eur. J. Immunol. 28:2508.[Medline]
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