Allorecognition of HLA-C mismatches by CD8+ T cells in hematopoietic stem cell transplantation is a complex interplay between mismatched peptide binding region residues, HLA-C expression and HLA-DPB1 disparities
HLA-C locus mismatches are the most frequent class I disparities in unrelated hematopoietic stem cell transplantation (HSCT) and have a detrimental impact on clinical outcome. Recently, a few retrospective clinical studies have reported some variability in the immunogenicity of HLA-C incompatibiliti...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2016-12-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fimmu.2016.00584/full |
| _version_ | 1818993201574313984 |
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| author | Florence Bettens Stépahne Buhler Jean-Marie Tiercy |
| author_facet | Florence Bettens Stépahne Buhler Jean-Marie Tiercy |
| author_sort | Florence Bettens |
| collection | DOAJ |
| description | HLA-C locus mismatches are the most frequent class I disparities in unrelated hematopoietic stem cell transplantation (HSCT) and have a detrimental impact on clinical outcome. Recently, a few retrospective clinical studies have reported some variability in the immunogenicity of HLA-C incompatibilities. To get better insight into presumably permissive HLA-C mismatches we have developed a one-way in vitro mixed lymphocyte reaction (MLR) assay allowing to quantify activated CD56-CD137+CD8+ lymphocytes in HLA-C incompatible combinations. T cell-mediated alloresponses were correlated with genetic markers such as HLA-C mRNA expression and the number of amino acid mismatches in the α1/α2 domains (peptide binding region). Because of the high rate of HLA-DPB1 incompatibilities in HLA-A, B, C, DRB1 and DQB1 matched unrelated HSCT patient/donor pairs, the impact of HLA-DPB1 mismatching, a potential bystander of CD4+ T cell activation, was also considered. Heterogeneous alloresponses were measured in 63 HLA-C mismatched pairs with a positive assay in 52% of the combinations (2.3-18.6% activated CTLs), representing 24 different HLA-A~B~DRB1~DQB1 haplotypes. There was no correlation between measured alloresponses and mRNA expression of the mismatched HLA-C alleles. The HLA-C*03:03/03:04 mismatch did not induce any positive alloresponse in 5 MLRs. We also identified HLA-C*02:02 and HLA-C*06:02 as mismatched alleles with lower immunogenicity, and HLA-C*14:02 as a more immunogenic mismatch. A difference of at least 10 amino acid residues known to impact peptide/TCR binding and a bystander HLA-DPB1 incompatibility had a significant impact on CTL alloreactivity (p=0.021). The same HLA-C mismatch, when recognized by two different responders with the same HLA haplotypes, was recognized differently, emphasizing the role of the T-cell repertoire of responding cells. In conclusion, mismatched HLA-C alleles differing by10 or more amino acids in the peptide/TCR binding region, when occurring together with HLA-DPB1 incompatibilities, should be considered as high risk mismatches in unrelated HSCT. |
| first_indexed | 2024-12-20T20:38:18Z |
| format | Article |
| id | doaj.art-53e85763fcc34785aa169fc3cf3fb69d |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-20T20:38:18Z |
| publishDate | 2016-12-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-53e85763fcc34785aa169fc3cf3fb69d2022-12-21T19:27:11ZengFrontiers Media S.A.Frontiers in Immunology1664-32242016-12-01710.3389/fimmu.2016.00584226066Allorecognition of HLA-C mismatches by CD8+ T cells in hematopoietic stem cell transplantation is a complex interplay between mismatched peptide binding region residues, HLA-C expression and HLA-DPB1 disparitiesFlorence Bettens0Stépahne Buhler1Jean-Marie Tiercy2Geneva University Hospital and Medical SchoolGeneva University Hospital and Medical SchoolGeneva University Hospital and Medical SchoolHLA-C locus mismatches are the most frequent class I disparities in unrelated hematopoietic stem cell transplantation (HSCT) and have a detrimental impact on clinical outcome. Recently, a few retrospective clinical studies have reported some variability in the immunogenicity of HLA-C incompatibilities. To get better insight into presumably permissive HLA-C mismatches we have developed a one-way in vitro mixed lymphocyte reaction (MLR) assay allowing to quantify activated CD56-CD137+CD8+ lymphocytes in HLA-C incompatible combinations. T cell-mediated alloresponses were correlated with genetic markers such as HLA-C mRNA expression and the number of amino acid mismatches in the α1/α2 domains (peptide binding region). Because of the high rate of HLA-DPB1 incompatibilities in HLA-A, B, C, DRB1 and DQB1 matched unrelated HSCT patient/donor pairs, the impact of HLA-DPB1 mismatching, a potential bystander of CD4+ T cell activation, was also considered. Heterogeneous alloresponses were measured in 63 HLA-C mismatched pairs with a positive assay in 52% of the combinations (2.3-18.6% activated CTLs), representing 24 different HLA-A~B~DRB1~DQB1 haplotypes. There was no correlation between measured alloresponses and mRNA expression of the mismatched HLA-C alleles. The HLA-C*03:03/03:04 mismatch did not induce any positive alloresponse in 5 MLRs. We also identified HLA-C*02:02 and HLA-C*06:02 as mismatched alleles with lower immunogenicity, and HLA-C*14:02 as a more immunogenic mismatch. A difference of at least 10 amino acid residues known to impact peptide/TCR binding and a bystander HLA-DPB1 incompatibility had a significant impact on CTL alloreactivity (p=0.021). The same HLA-C mismatch, when recognized by two different responders with the same HLA haplotypes, was recognized differently, emphasizing the role of the T-cell repertoire of responding cells. In conclusion, mismatched HLA-C alleles differing by10 or more amino acids in the peptide/TCR binding region, when occurring together with HLA-DPB1 incompatibilities, should be considered as high risk mismatches in unrelated HSCT.http://journal.frontiersin.org/Journal/10.3389/fimmu.2016.00584/fullStem Cell Transplantationalloreactivityin vitro culturecytotoxic T lymphocyte (CTL)HLA-C |
| spellingShingle | Florence Bettens Stépahne Buhler Jean-Marie Tiercy Allorecognition of HLA-C mismatches by CD8+ T cells in hematopoietic stem cell transplantation is a complex interplay between mismatched peptide binding region residues, HLA-C expression and HLA-DPB1 disparities Frontiers in Immunology Stem Cell Transplantation alloreactivity in vitro culture cytotoxic T lymphocyte (CTL) HLA-C |
| title | Allorecognition of HLA-C mismatches by CD8+ T cells in hematopoietic stem cell transplantation is a complex interplay between mismatched peptide binding region residues, HLA-C expression and HLA-DPB1 disparities |
| title_full | Allorecognition of HLA-C mismatches by CD8+ T cells in hematopoietic stem cell transplantation is a complex interplay between mismatched peptide binding region residues, HLA-C expression and HLA-DPB1 disparities |
| title_fullStr | Allorecognition of HLA-C mismatches by CD8+ T cells in hematopoietic stem cell transplantation is a complex interplay between mismatched peptide binding region residues, HLA-C expression and HLA-DPB1 disparities |
| title_full_unstemmed | Allorecognition of HLA-C mismatches by CD8+ T cells in hematopoietic stem cell transplantation is a complex interplay between mismatched peptide binding region residues, HLA-C expression and HLA-DPB1 disparities |
| title_short | Allorecognition of HLA-C mismatches by CD8+ T cells in hematopoietic stem cell transplantation is a complex interplay between mismatched peptide binding region residues, HLA-C expression and HLA-DPB1 disparities |
| title_sort | allorecognition of hla c mismatches by cd8 t cells in hematopoietic stem cell transplantation is a complex interplay between mismatched peptide binding region residues hla c expression and hla dpb1 disparities |
| topic | Stem Cell Transplantation alloreactivity in vitro culture cytotoxic T lymphocyte (CTL) HLA-C |
| url | http://journal.frontiersin.org/Journal/10.3389/fimmu.2016.00584/full |
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