The allogeneic HLA-DP-restricted T-cell repertoire provoked by allogeneic dendritic cells contains T cells that show restricted recognition of hematopoietic cells including primary malignant cells

Laghmouchi, Aicha; Hoogstraten, Conny; Balen, Peter van; Falkenburg, J.H. Frederik; Jedema, Inge

doi:10.3324/haematol.2018.193680

Cited by 8 publications

(9 citation statements)

References 42 publications

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“…CD4 T-cell clones recognizing only stimulator cells expressing the mismatched target HLA-DP allele(s) and not stimulator cells expressing the autologous HLA-DP allele(s) were selected as being allo-HLA-DP reactive, as described previously ( 39 , 42 ). The reactivity of allo-HLA-DP-reactive T-cell clones against different HLA-DP molecules was analyzed using the panel of HLA-DP-transduced K562 cell lines as stimulator cells at a 1:5 responder to stimulator ratio in IMDM/10% ABOS supplemented with 25 IU/ml IL-2.…”

Section: Methodsmentioning

confidence: 99%

Promiscuity of Peptides Presented in HLA-DP Molecules from Different Immunogenicity Groups Is Associated With T-Cell Cross-Reactivity

et al. 2022

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In the context of HLA-DP-mismatched allogeneic stem cell transplantation, mismatched HLA-DP alleles can provoke profound allo-HLA-DP-specific immune responses from the donor T-cell repertoire leading to graft-versus-leukemia effect and/or graft-versus-host disease in the patient. The magnitude of allo-HLA-DP-specific immune responses has been shown to depend on the specific HLA-DP disparity between donor and patient and the immunogenicity of the mismatched HLA-DP allele(s). HLA-DP peptidome clustering (DPC) was developed to classify the HLA-DP molecules based on similarities and differences in their peptide-binding motifs. To investigate a possible categorization of HLA-DP molecules based on overlap of presented peptides, we identified and compared the peptidomes of the thirteen most frequently expressed HLA-DP molecules. Our categorization based on shared peptides was in line with the DPC classification. We found that the HLA-DP molecules within the previously defined groups DPC-1 or DPC-3 shared the largest numbers of presented peptides. However, the HLA-DP molecules in DPC-2 segregated into two subgroups based on the overlap in presented peptides. Besides overlap in presented peptides within the DPC groups, a substantial number of peptides was also found to be shared between HLA-DP molecules from different DPC groups, especially for groups DPC-1 and -2. The functional relevance of these findings was illustrated by demonstration of cross-reactivity of allo-HLA-DP-reactive T-cell clones not only against HLA-DP molecules within one DPC group, but also across different DPC groups. The promiscuity of peptides presented in various HLA-DP molecules and the cross-reactivity against different HLA-DP molecules demonstrate that these molecules cannot be strictly categorized in immunogenicity groups.

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Section: Methodsmentioning

confidence: 99%

Promiscuity of Peptides Presented in HLA-DP Molecules from Different Immunogenicity Groups Is Associated With T-Cell Cross-Reactivity

et al. 2022

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“…It was already shown by others that HLA-DP specific T cells with reactivity pattern restricted to hematopoietic cells can indeed be generated [36]. Therefore, extensive screening for such TCRs seems to be a reasonable strategy.…”

Section: Discussionmentioning

confidence: 99%

HLA-DPB1 Reactive T Cell Receptors for Adoptive Immunotherapy in Allogeneic Stem Cell Transplantation

Klobuch

Hammon

Vatter-Leising

et al. 2020

Cells

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HLA-DPB1 antigens are mismatched in about 80% of allogeneic hematopoietic stem cell transplantations from HLA 10/10 matched unrelated donors and were shown to be associated with a decreased risk of leukemia relapse. We recently developed a reliable in vitro method to generate HLA-DPB1 mismatch-reactive CD4 T-cell clones from allogeneic donors. Here, we isolated HLA-DPB1 specific T cell receptors (TCR DP) and used them either as wild-type or genetically optimized receptors to analyze in detail the reactivity of transduced CD4 and CD8 T cells toward primary AML blasts. While both CD4 and CD8 T cells showed strong AML reactivity in vitro, only CD4 T cells were able to effectively eliminate leukemia blasts in AML engrafted NOD/SCID/IL2Rγc−/− (NSG) mice. Further analysis showed that optimized TCR DP and under some conditions wild-type TCR DP also mediated reactivity to non-hematopoietic cells like fibroblasts or tumor cell lines after HLA-DP upregulation. In conclusion, T cells engineered with selected allo-HLA-DPB1 specific TCRs might be powerful off-the-shelf reagents in allogeneic T-cell therapy of leukemia. However, because of frequent (common) cross-reactivity to non-hematopoietic cells with optimized TCR DP T cells, safety mechanisms are mandatory.

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“…The scope our current study was not to fully unravel the recognized allogeneic peptide in allo-HLA molecules. However, this may demonstrate that allo-HLA cross-reactive T cells do not solely recognize an household peptide in the context of allogeneic HLA, but potentially also lineage-specific peptide-allo-HLA cross-reactivity exists ( 28 ). Also recognition of HLA-class-II molecules by HLA-class-I-restricted CD8 pos virus-specific T cells has previously been described ( 11 ).…”

Section: Discussionmentioning

confidence: 99%

Magnitude of Off-Target Allo-HLA Reactivity by Third-Party Donor-Derived Virus-Specific T Cells Is Dictated by HLA-Restriction

et al. 2021

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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.

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The allogeneic HLA-DP-restricted T-cell repertoire provoked by allogeneic dendritic cells contains T cells that show restricted recognition of hematopoietic cells including primary malignant cells

Cited by 8 publications

References 42 publications

Promiscuity of Peptides Presented in HLA-DP Molecules from Different Immunogenicity Groups Is Associated With T-Cell Cross-Reactivity

Promiscuity of Peptides Presented in HLA-DP Molecules from Different Immunogenicity Groups Is Associated With T-Cell Cross-Reactivity

HLA-DPB1 Reactive T Cell Receptors for Adoptive Immunotherapy in Allogeneic Stem Cell Transplantation

Magnitude of Off-Target Allo-HLA Reactivity by Third-Party Donor-Derived Virus-Specific T Cells Is Dictated by HLA-Restriction

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