Magnitude of Off-Target Allo-HLA Reactivity by Third-Party Donor-Derived Virus-Specific T Cells Is Dictated by HLA-Restriction
T-cell products derived from third-party donors are clinically applied, but harbor the risk of off-target toxicity via induction of allo-HLA cross-reactivity directed against mismatched alleles. We used third-party donor-derived virus-specific T cells as model to investigate whether virus-specificit...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.630440/full |
| _version_ | 1818873589245411328 |
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| author | Wesley Huisman Wesley Huisman Didier A. T. Leboux Lieve E. van der Maarel Lois Hageman Derk Amsen J. H. Frederik Falkenburg Inge Jedema |
| author_facet | Wesley Huisman Wesley Huisman Didier A. T. Leboux Lieve E. van der Maarel Lois Hageman Derk Amsen J. H. Frederik Falkenburg Inge Jedema |
| author_sort | Wesley Huisman |
| collection | DOAJ |
| description | T-cell products derived from third-party donors are clinically applied, but harbor the risk of off-target toxicity via induction of allo-HLA cross-reactivity directed against mismatched alleles. We used third-party donor-derived virus-specific T cells as model to investigate whether virus-specificity, HLA restriction and/or HLA background can predict the risk of allo-HLA cross-reactivity. Virus-specific CD8pos T cells were isolated from HLA-A*01:01/B*08:01 or HLA-A*02:01/B*07:02 positive donors. Allo-HLA cross-reactivity was tested using an EBV-LCL panel covering 116 allogeneic HLA molecules and confirmed using K562 cells retrovirally transduced with single HLA-class-I alleles of interest. HLA-B*08:01-restricted T cells showed the highest frequency and diversity of allo-HLA cross-reactivity, regardless of virus-specificity, which was skewed toward multiple recurrent allogeneic HLA-B molecules. Thymic selection for other HLA-B alleles significantly influenced the level of allo-HLA cross-reactivity mediated by HLA-B*08:01-restricted T cells. These results suggest that the degree and specificity of allo-HLA cross-reactivity by T cells follow rules. The risk of off-target toxicity after infusion of incompletely matched third-party donor-derived virus-specific T cells may be reduced by selection of T cells with a specific HLA restriction and background. |
| first_indexed | 2024-12-19T12:57:06Z |
| format | Article |
| id | doaj.art-98f2725cc9f64cd1bfd462fb0ce03440 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-19T12:57:06Z |
| publishDate | 2021-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-98f2725cc9f64cd1bfd462fb0ce034402022-12-21T20:20:21ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-03-011210.3389/fimmu.2021.630440630440Magnitude of Off-Target Allo-HLA Reactivity by Third-Party Donor-Derived Virus-Specific T Cells Is Dictated by HLA-RestrictionWesley Huisman0Wesley Huisman1Didier A. T. Leboux2Lieve E. van der Maarel3Lois Hageman4Derk Amsen5J. H. Frederik Falkenburg6Inge Jedema7Department of Hematology, Leiden University Medical Center, Leiden, NetherlandsDepartment of Hematopoiesis, Sanquin Research and Landsteiner Laboratory for Blood Cell Research, Amsterdam, NetherlandsDepartment of Hematology, Leiden University Medical Center, Leiden, NetherlandsDepartment of Hematology, Leiden University Medical Center, Leiden, NetherlandsDepartment of Hematology, Leiden University Medical Center, Leiden, NetherlandsDepartment of Hematopoiesis, Sanquin Research and Landsteiner Laboratory for Blood Cell Research, Amsterdam, NetherlandsDepartment of Hematology, Leiden University Medical Center, Leiden, NetherlandsDepartment of Hematology, Leiden University Medical Center, Leiden, NetherlandsT-cell products derived from third-party donors are clinically applied, but harbor the risk of off-target toxicity via induction of allo-HLA cross-reactivity directed against mismatched alleles. We used third-party donor-derived virus-specific T cells as model to investigate whether virus-specificity, HLA restriction and/or HLA background can predict the risk of allo-HLA cross-reactivity. Virus-specific CD8pos T cells were isolated from HLA-A*01:01/B*08:01 or HLA-A*02:01/B*07:02 positive donors. Allo-HLA cross-reactivity was tested using an EBV-LCL panel covering 116 allogeneic HLA molecules and confirmed using K562 cells retrovirally transduced with single HLA-class-I alleles of interest. HLA-B*08:01-restricted T cells showed the highest frequency and diversity of allo-HLA cross-reactivity, regardless of virus-specificity, which was skewed toward multiple recurrent allogeneic HLA-B molecules. Thymic selection for other HLA-B alleles significantly influenced the level of allo-HLA cross-reactivity mediated by HLA-B*08:01-restricted T cells. These results suggest that the degree and specificity of allo-HLA cross-reactivity by T cells follow rules. The risk of off-target toxicity after infusion of incompletely matched third-party donor-derived virus-specific T cells may be reduced by selection of T cells with a specific HLA restriction and background.https://www.frontiersin.org/articles/10.3389/fimmu.2021.630440/fullvirus-specific T cellsallo-HLA cross-reactivityadoptive T cell immunotherapyHLA-mismatched donorcytotoxic T cellsGraft Versus Host Disease |
| spellingShingle | Wesley Huisman Wesley Huisman Didier A. T. Leboux Lieve E. van der Maarel Lois Hageman Derk Amsen J. H. Frederik Falkenburg Inge Jedema Magnitude of Off-Target Allo-HLA Reactivity by Third-Party Donor-Derived Virus-Specific T Cells Is Dictated by HLA-Restriction Frontiers in Immunology virus-specific T cells allo-HLA cross-reactivity adoptive T cell immunotherapy HLA-mismatched donor cytotoxic T cells Graft Versus Host Disease |
| title | Magnitude of Off-Target Allo-HLA Reactivity by Third-Party Donor-Derived Virus-Specific T Cells Is Dictated by HLA-Restriction |
| title_full | Magnitude of Off-Target Allo-HLA Reactivity by Third-Party Donor-Derived Virus-Specific T Cells Is Dictated by HLA-Restriction |
| title_fullStr | Magnitude of Off-Target Allo-HLA Reactivity by Third-Party Donor-Derived Virus-Specific T Cells Is Dictated by HLA-Restriction |
| title_full_unstemmed | Magnitude of Off-Target Allo-HLA Reactivity by Third-Party Donor-Derived Virus-Specific T Cells Is Dictated by HLA-Restriction |
| title_short | Magnitude of Off-Target Allo-HLA Reactivity by Third-Party Donor-Derived Virus-Specific T Cells Is Dictated by HLA-Restriction |
| title_sort | magnitude of off target allo hla reactivity by third party donor derived virus specific t cells is dictated by hla restriction |
| topic | virus-specific T cells allo-HLA cross-reactivity adoptive T cell immunotherapy HLA-mismatched donor cytotoxic T cells Graft Versus Host Disease |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.630440/full |
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