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Original Article |
vhe{at}virginia.edu
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Key Words: minor histocompatibility antigens • antigen processing • graft versus host disease • transplantation • Fourier transform mass spectrometry
mHAgs have been shown to be peptides derived from normal cellular proteins that are presented by MHC class I and II molecules 1213. Over 50 different mHAg genetic loci have been defined among inbred strains of mice 14, whereas the number in humans is unknown. Due to the difficulty of identifying mHAg peptides, a full understanding of the basis for minor antigenic disparities has yet to be achieved. It is generally believed that identification of a more extensive array of mHAg peptides and their cognate genes will lead to improvements in pre-BMT donor and recipient typing 15 and, in the more distant future, immunomodulatory strategies to decrease GVHD incidence and severity as well as graft rejection.
The structure, genetics, and tissue distribution of several human mHAgs have been studied by using specific T cells isolated from allogeneic BMT patients 161718192021. The use of such T cells, together with either direct peptide extraction and mass spectrometry 2223242526 or cDNA cloning 2127, has led to the successful identification of seven peptides corresponding to human mHAgs. In this report, we describe the identification of the amino acid and nucleotide sequences of an HLA-A*0201–restricted mHAg, termed HA-8, as well as its negative polymorphic counterparts. Our results provide the first evidence that the existence of mHAg can result from altered processing of immunologically similar peptides rather than differences in interaction with the relevant MHC molecule or T cell receptor.
Extraction and HPLC Fractionation of Immunoaffinity-purified, HLA-A*0201–associated Peptides.
Epitope Reconstitution Assays.
Peptide Analysis Using an Online Effluent Splitter and a Fourier Transform Mass Spectrometer.
Sequence Analysis of Candidate Antigens.
Synthetic Peptides.
Class I Peptide-binding Affinity Assay.
Reverse Transcription PCR Amplification and Sequencing of the KIAA0020 Region Encoding the HA-8 mHAg.
Genotyping of HA-8 mHAg Polymorphisms.
Expression Plasmids Encoding the HA-8 mHAg and Its Homologues.
Streptolysin O Peptide Transport Assay.
Introduction
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Bone marrow transplantation (BMT) is a crucial therapy for hematological malignancies. Its therapeutic efficacy can be attributed in part to the beneficial graft versus leukemia effect in which residual host leukemic cells are eliminated by mature donor-derived T cells present in the bone marrow inoculum 1. Although mature donor-derived T cells facilitate graft acceptance, their reactivity against minor histocompatibility antigens (mHAgs) expressed by the recipient also leads to GVHD 23456789, and the administration of immunosuppressive drugs after allogeneic bone marrow transplants is essential to reduce morbidity and mortality 61011.
Materials and Methods
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Cell Culture.
The HA-8 mHAg-specific, HLA-A*0201–restricted CD8+ CTL clone (designated SKH-13 CTL) was derived from the PBLs of a male patient who received a BMT from his HLA-identical sister for chronic myelogenous leukemia. This CTL clone was used in cytotoxicity and epitope reconstitution assays either 11–15 d after stimulation as described previously 28, or 1–3 d after thawing a frozen aliquot. HLA-A*0201+ EBV–transformed B cell lines (BLCLs) include SDK (donor), SKH (recipient), JY, RSR, JDR, Ruppen, and C1R-A2. BLCLs from the Centre d'Étude du Polymorphisme Humain (CEPH) (Paris, France; reference family 1362) were a gift from Dr. S.M. Prescott and the Huntsman Cancer Institute, University of Utah (Salt Lake City, UT). The TxB cell hybrids T1 and T2, which are positive and negative for the transporter associated with antigen processing (TAP), respectively, were obtained from Dr. P. Cresswell (Yale University, New Haven, CT). BLCLs and hybrids were maintained in RPMI 1640 supplemented with 4 mM Hepes, 5% FCS, 0.125% SerXtend (Irvine Scientific), and 3 mM L-glutamine (BLCL medium). In some experiments, the CEPH BLCLs were infected with a recombinant vaccinia virus that encodes HLA-A*0201 (a gift of Dr. J. Yewdell, National Institute of Allergy and Infectious Diseases, Bethesda, MD) at a multiplicity of infection of 5:1, 18 h before use in cytotoxicity assays. High-level cell surface expression of HLA-A2 was confirmed with flow cytometry, and uninfected and wild-type vaccinia–infected cells were used as controls.
HLA-A*0201 molecules were immunoaffinity purified from JY cells with mAb BB7.2 29 and their associated peptides were extracted as described previously 25. The peptide extract was fractionated on a narrow bore HAISIL C18 column (2.1 x 40 mm, 5 µm particles, 300 Å pore size; Higgins) on 130A HPLC (Applied Biosystems). The elution gradient used was 0–10% solvent B in 10 min, 10–60% B in the next 55 min, and 60–100% B in the next 7 min, where solvent A was 0.1% TFA (HPLC grade; Applied Biosystems) in NANOpure water (Barnstead) and solvent B was 0.085% TFA in 60% acetonitrile (HPLC grade; Mallinckrodt) in NANOpure water. Fractions were collected every 40 s at a flow rate of 200 µl/min. Active fractions were pooled and rechromatographed with the identical column and gradient, but using 0.1% heptafluorobutyric acid (HFBA) as the ion-pairing agent. Half of the active second dimension material was used for a third dimension fractionation on a microcapillary 30 column (280 µm outer diameter [OD], 75 µm inner diameter [ID]) packed with 25 cm of 5 µm C18 beads (YMC). TFA was used as the ion-pairing agent in buffers A and B described above, and the column was eluted with a linear gradient of 0–100% B over 40 min at a flow rate of 300 nl/min.
Aliquots of each HPLC fraction were incubated with 2,000 51Cr-labeled, TAP-deficient T2 target cells and 7.5 µg/ml human β2-microglubulin (Calbiochem) for 30 min at 37°C in 150 µl BLCL medium. CTLs were added in 100 µl BLCL medium at an E/T of 10:1 in a standard 51Cr-release assay 22. Synthetic peptides were assayed using the same protocol.
Active third dimension HPLC fractions were analyzed by electrospray ionization (ESI) on a Fourier transform mass spectrometer (FTMS) equipped with nanoflow liquid chromatography and a modified online effluent splitter 313233. Samples were fractionated using a microcapillary HPLC column (50 µm ID; reference 30) packed with 12 cm of 5 µm C18 beads (YMC) and a 45-min gradient of 0–86% solvent B (solvent A is 0.1 M acetic acid in water; solvent B is 0.1 M acetic acid in 70% acetonitrile) flowing at 825 nl/min. The online splitter directed 1/8 of the effluent to the FTMS for analysis and 7/8 into microtiter plate wells containing 25 µl NANOpure water, which was reserved for epitope reconstitution assays.
Collision-activated dissociation (CAD) mass spectra were recorded on selected peptide candidates using a Finnigan LCQ ion trap MS equipped with sheathless nanoflow HPLC-ESI as described previously 32. Data were acquired by manually switching from MS-only mode to MS/MS mode after the chromatographic elution of a marker peptide. In MS/MS mode, the ion of interest was isolated using a 3.0 atomic mass unit isolation window and fragmented using 35% collision energy. CAD spectra were analyzed in a manual search of the GenBank/EMBL/DDBJ DNA and protein databases.
Peptides were synthesized on an AMS 1400 multiple peptide synthesizer (Gilson Medical Electronics) using solid-phase FMOC chemistry and Wang resins. Peptides were HPLC purified to >98% on a C-8 column (Vydac). Purity and identity of all synthetic peptides were confirmed using ESI with an LCQ MS.
Relative affinities of peptides for HLA-A*0201 molecules were measured as described 34. In brief, affinity-purified HLA-A*0201 molecules were incubated at room temperature with an 125I-labeled indicator peptide (FLPSDYFPSV) and graded doses of test peptides in PBS, pH 7.0, containing 0.05% NP-40, 1 µM human β2-microglubulin (Calbiochem), 1 mM PMSF, 1.3 mM 1,10-phenanthroline, 73 µM pepstatin A, 8 mM EDTA, and 200 µM N
-p-tosyl-L-lysine chloromethyl ketone. After 48 h, class I peptide complexes were separated from free peptides by gel filtration, and the dose of individual test peptides that reduced the binding of indicator peptide by 50% (IC50) was calculated.
Poly(A)+ RNA was isolated with a QuickPrep Micro mRNA Purification kit (Amersham Pharmacia Biotech), and cDNA was synthesized using a First Strand cDNA synthesis kit (MBI Fermentas). Amplifications were performed with 0.5 µmol each of forward primer 5'-ATCAGAAGTTTTAAAGGCCAC-3' and reverse primer 5'-GCTTCAATCATTTCTGATCTG-3'. Products were purified with the Wizard PCR Preps DNA purification system (Promega) and cloned using the AdvanTAge cloning kit (CLONTECH Laboratories, Inc.). At least five individual clones were sequenced bidirectionally for each cell line examined.
Genomic DNA was isolated from BLCLs with a Puregene kit (Gentra Systems). Adjacent intronic sequence required for genomic PCR analysis was obtained from a genomic DNA library constructed by TA cloning 35. Amplifications were performed with the allele-specific forward primers 5'-GTCAGCAGATCACCG-3' (HA-8R) and 5'-GTCAGCAGATCACCC-3' (HA-8P and HA-8PL), and a common reverse primer 5'-GGGCAACAGTTATGGA-3'. BLCLs were also genotyped using a modified PCR-RFLP technique 36. The forward primer 5'-ggatatacagcagagctttc-3' was used with the antisense primer 5'- TCTAACACTTTGTCCCAGAATT-3'. The underlined A is normally G in the KIAA0020 sequence and was substituted such that an EcoRI site is created only when the primer anneals to the HA-8R allele. PCR products were digested with EcoRI and analyzed on a 2.5% agarose gel. HA-8P and HA-8PL polymorphisms produced a single 183-bp band, whereas the HA-8R allele produced 165- and 22-bp bands.
Minigene expression constructs encoding RTLDKVLEV, PTLDKVLEV, or PTLDKVLEV, with or without the adenovirus E3-19K endoplasmic reticulum (ER) insertion sequence 37, were constructed using the pEAK10 vector (Edge Bio Systems). The constructs all encoded a Kozak sequence and initiator methionine (AGCTTCCACCATG) and a stop codon (TTA). All products were ligated into HindIII-NotI cut pEAK10 and verified by sequencing. Additional expression plasmids were constructed that encoded truncated proteins corresponding to the HA-8R, HA-8P, and HA-8PL alleles. These initiate from the native start codon, include the peptides corresponding to the HA-8 mHAg and its alleles at residues 149–157, and terminate at the predicted amino acid 223. Products containing these sequences were reverse transcription (RT)-PCR amplified using a 5' primer containing a HindIII site, the native Kozak sequence and start codon, and a 3' primer containing the KIAA0020 sequence up to nucleotide 1087, an in-frame stop codon, and a NotI site. All constructs were introduced into SDK BLCLs by electroporation, followed by incubation in BLCL medium for 48 h and selection with puromycin (0.7 µg/ml; Edge Bio Systems) for an additional 48 h before use in cytolytic assays.
In vitro assays of TAP-mediated peptide transport were performed as described previously 38, with modifications. T1 cells (106/sample) were permeabilized on ice for 15 min with streptolysin O (15 U/ml; Murex Diagnostics) and incubated for 5 min at 37°C with 100 ng of the reporter peptide TVNKTERAY (reference 39; radiolabeled with Na125I using the chloramine T method; reference 40), 10 µl 100 mM ATP, and indicated dilutions of competitor peptides. The reporter peptide contains an N-linked glycosylation site (Asn-X-Thr/Ser) and will become glycosylated after translocation by TAP into the ER. Glycosylated reporter peptide was isolated using Con A–Sepharose (Amersham Pharmacia Biotech), eluted with 0.2 M methyl -D-mannopyranoside (Sigma-Aldrich), and quantitated on a 
counter. Reporter peptide transport in TAP-negative T2 cells was assessed as a negative control. Samples were done in duplicate except for T2 negative control and T1 cells with no inhibitor, which were done in triplicate.
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Mass Spectrometric Identification of the HA-8 mHAg Epitope.
To identify the mHAg recognized by CTL clone SKH-13, HLA-A*0201–associated peptides were purified from the BLCL JY and fractionated by reverse phase (RP)-HPLC. Fractions were analyzed for their ability to reconstitute CTL recognition using TAP-deficient T2 cells as target cells and the SKH-13 CTLs as effector cells in a 51Cr-release assay. Active fractions were pooled and carried forward into another round of RP-HPLC under different conditions. Single peaks of reconstituting activity were observed through three rounds of fractionation (Fig. 1). Candidate masses for the HA-8 mHAg were identified by an online effluent splitter analysis of the third dimension active fractions using a combination of nanoflow liquid chromatography with ESI on an FTMS 26. By comparing the abundance of peptide ions in spectra from wells that showed epitope reconstituting activity with SKH-13 CTLs, five candidate peptides were identified (Fig. 1 D).
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50 pM (Fig. 2 C). Of the four possible isomers containing either Leu or Ile in place of X in this sequence, only the form containing Leu at both P3 and P7 coeluted from a microcapillary HPLC column with the naturally processed peptide m/z 536.834+2 (data not shown). By comparing the signal intensity of the naturally occurring peptide with a known amount of synthetic RTLDKVLEV, we calculated that this mHAg is present at 10 copies per BLCL (data not shown). Target cells pulsed with the RTLDKVLEV peptide were lysed by SKH-13 CTLs, with half-maximal activity seen at a peptide concentration of 20 pM (Fig. 2 C). RTLDKVLEV additionally reconstitutes CTL lysis when incubated with SDK, a BLCL derived from the HLA-identical sibling donor (data not shown). Thus, RTLDKVLEV defines the HLA-A*0201–restricted HA-8 mHAg epitope.
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RT-PCR primers (represented by black bars in Fig. 3) that amplified a 347-bp cDNA product surrounding the epitope were generated from sequences that were identical among KIAA0020, AA307160, and AA478933 but not conserved in the chromosome 18–encoded sequence. Consistent with the finding that the HA-8 mHAg sequence RTLDKVLEV is encoded by KIAA0020, sequences identical to KIAA0020 were amplified from all four BLCLs that were recognized by SKH-13 CTLs (Table ). The only RT-PCR products amplified from the three BLCLs not recognized by SKH-13 CTLs were identical to N90372 (with the exception of two ambiguous nucleotides in the N90372 sequence; Fig. 3). The absence of the KIAA0020 sequence, together with the presence of the N90372 sequence, is consistent with the hypothesis that these represent alleles of the same gene. The polymorphic nucleotide sequences corresponding to KIAA0020 and N90372 were designated HA-8R and HA-8P, respectively.
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Further evidence for this hypothesis was obtained by screening all individuals in three consecutive generations of a large family for expression of the HA-8 mHAg, and correlating the results with their genotype at the KIAA0020 locus. BLCLs derived from each individual in CEPH reference family 1362 were infected with a recombinant vaccinia virus expressing the HLA-A*0201 gene and tested for HA-8 expression with SKH-13 CTLs (Fig. 5). The genotype of each individual at nucleotide 864 in the KIAA0020 cDNA sequence, which determines either an R or P in P1 of the epitope recognized by the SKH-13 CTL clone, was determined by testing genomic DNA derived from each BLCL with a PCR-RFLP assay that distinguishes between G and C at this position. All HA-8– members of the CEPH family 1362 exhibited the HA-8P sequence, whereas all HA-8+ members expressed both HA-8R and HA-8P (Fig. 5). These results confirm that the KIAA0020 gene has at least two alleles, of which only HA-8R leads to specific CTL recognition.
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90 nM) than recognition of RTLDKVLEV (20 pM). This difference is larger than the difference in HLA-A*0201 binding affinity, suggesting that the substitutions at P1 and P9 have an additional detrimental effect on CTL recognition. However, recognition of PTLDKVLEV required only 15-fold more peptide (half-maximal lysis of 300 pM). Taking into account the differences in binding affinity, this suggests that SKH-13 CTL recognizes PTLDKVLEV as well as or better than RTLDKVLEV. This stands in contrast to the complete lack of recognition of donor-derived (self) SDK BLCL cells or cells that are homozygous for HA-8P (Table , Fig. 5, and data not shown). These results suggested that differences in MHC binding and CTL recognition did not account for the failure of SKH-13 CTLs to recognize cells that were homozygous for HA-8P and that differences in antigen processing might instead be responsible.
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In principle, any genetic polymorphism that qualitatively or quantitatively affects the display of self-peptides at the cell surface could give rise to an mHAg disparity in an MHC identical transplantation setting 13. These can be classified based on their impact on either T cell recognition or peptide presentation by MHC molecules. In the case of the human mHAgs B7-HY 23 and A1-HY 26, and mouse mHAg MTF 42, the mHAg– alleles encode polymorphic peptides that retain their ability to bind to the relevant MHC molecule. The existence of these mHAgs is thus dependent on the presence within any individual of TCR with an appropriate fine specificity to distinguish mHAg-expressing cells from their negative counterparts. In some cases, T cell discrimination may be augmented by the presence of posttranslational modifications on the mHAg+ allelic peptides 2526. TCR discrimination between two presented peptides has been proposed to define the human HB-1 mHAg 27, the murine mHAgs H3a 43 and H13 44, and the rat MTF mHAg 45. However, endogenous presentation of the mHAg– peptide has not been formally demonstrated in any of these cases.
Two additional mechanisms in which the corresponding negative allelic peptides are not presented at the cell surface enable mHAgs to be distinguished by T cells. This type of differential display may enable a more robust T cell response, since it will not be limited to TCRs that can make fine distinctions among closely related peptides. In one case, mHAgs are distinguished due to polymorphisms that diminish or abolish the ability of the mHAg– peptide to bind to the relevant MHC molecule. This mechanism underlies the immunogenicity of the human mHAg HA-1 24 and the murine mHAg HY-Db 46. A second possibility is that the mHAg-positive and -negative peptides are antigenically similar, but are handled differently by the antigen processing machinery of the cell. Such a possibility has not been previously described for mHAgs.
A critical observation in the present study is that HLA-A*0201+ cells expressing HA-8P and HA-8PL genes or minigene fragments in the cytosol are not recognized by SKH-13 CTLs, yet PTLDKVLEV as an exogenously pulsed or ER translocated peptide is recognized nearly as well as the HA-8 mHAg peptide RTLDKVLEV. This observation could indicate that either PTLDKVLEV or its precursors are transported poorly by TAP, or that differences between the HA-8R and HA-8P protein products lead either to a failure to produce the PTLDKVLEV epitope or to its destruction by the proteasome or other cellular proteases. It is noteworthy that in comparing the cDNA sequences of a 347-bp region surrounding the epitope in the seven HA-8+ and HA-8– BLCLs listed in Table , the only polymorphisms were at the P1 and P9 positions within the epitope (data not shown). In addition, the ability of PTLDKVLEV to be recognized by the SKH-13 CTLs when targeted to the ER with an NH2-terminally fused E3-19K signal sequence argues against substantial degradation of this peptide by aminopeptidases in the ER 4748. Differential proteolysis in the cytosol is one possible explanation for the failure of HA-8– cells to present PTLDKVLEV. Previous studies have demonstrated that subunit-independent proteasomal cleavage is augmented three residues to the COOH terminal side of a P 4950. This could result in greater destruction of the PTLDKVLEV epitope. On the other hand, we observed that PTLDKVLEV, as well as PTLDKVLEV-containing peptides with additional natural NH2-terminal flanking amino acids, are translocated into the ER in vitro appreciably less well than RTLDKVLEV and its analogous NH2-terminally extended peptides. This is consistent with previous studies showing that peptides containing a P at P1 or P2 are generally transported poorly by human, mouse, and rat TAP 515253, whereas positively charged residues, and particularly R at P1–P3, enhanced TAP interaction 52. It is interesting that even in comparing the 14-mer peptides KSADHPTLDKVLEV and KSADHRTLDKVLEV in this study, the presence of P at P6 also diminished peptide transport by TAP. Thus, while the exact epitope-containing substrates for TAP transport in vivo have not been identified, our data suggest that those derived from HA-8P and HA-8PL will be poorly transported by TAP. Taken together, our results suggest that the basis for lack of immunogenicity of endogenous PTLDKVLEV lies not in differential recognition of the peptide by the HA-8–specific TCR, but rather in its inability to be productively transported by TAP for presentation by HLA-A*0201 at the cell surface. Thus, HA-8R represents the first mHAg that has been shown to result from differential antigen processing and this may represent an important mechanism for the generation of mHAgs.
The elucidation of mHAg peptides and their cognate genes forms a critical foundation for future attempts to improve the outcome of MHC-identical, mHAg-mismatched BMT, or solid organ transplants. The HA-8 mHAg is present in the population at a phenotype frequency of 65%. Additionally, HA-8 is presented by the HLA-A*0201 restriction element, which has a high phenotype frequency in most populations (i.e., 49% in the Caucasian population). This suggests that BMT donor and recipient pairs will often be discordant for this mHAg. Although the significance of the HA-8 mHAg in GVHD or graft rejection remains to be determined, the genotyping reagents described in this study will allow prospective studies of association between HA-8 incompatibility and outcomes after transplantation. The prospect of using the DNA sequences encoding mHAgs in pre-BMT molecular typing to improve donor selection or as a prognostic indicator of GVHD/graft rejection risk becomes increasingly more attainable with the identification of each new mHAg peptide. In the more distant future, potential applications may include tolerance induction in solid organ and bone marrow transplant and the design of prophylaxis against GVHD and rejection.
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Acknowledgments |
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Submitted: 23 August 2000
Revised: 7 December 2000
Accepted: 8 December 2000
Abbreviations used in this paper: BMT, bone marrow transplantation; CAD, collision-activated dissociation; CEPH, Centre d'Étude du Polymorphisme Humain; ER, endoplasmic reticulum; ESI, electrospray ionization; FTMS, Fourier transform MS; HFBA, heptafluorobutyric acid; ID, inner diameter; mHAg, minor histocompatibility antigen; MS, mass spectrometer; RP, reverse phase; RT, reverse transcription; TAP, transporter associated with antigen processing.
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) to affinity-purified HLA-A*0201 molecules in a cell-free peptide binding assay (see Materials and Methods). (B) RTLDKVLEV, PTLDKVLEV, and PTLDKVLEL were tested for their ability to reconstitute the epitope for the SKH-13 CTL clone. Epitope reconstitution assay conditions are described in Materials and Methods. An E/T ratio of 10:1 was used. Background CTL lysis of T2 in the absence of any peptides was 4%; positive control lysis (SKH) was 80%.
