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

Huisman, Wesley; Leboux, Didier A.T.; Maarel, Lieve E. van der; Hageman, Lois; Amsen, Derk; Falkenburg, J.H. Frederik; Jedema, Inge

doi:10.3389/fimmu.2021.630440

Cited by 8 publications

(14 citation statements)

References 42 publications

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“…Allo-HLA-reactive T cells are present within all normal T-cell repertoires, since during thymic selection, T cells capable of recognizing peptides in the context of allogeneic HLA molecules are not deleted as they do not encounter these foreign HLA molecules during T-cell development (23,24). T cells capable of recognizing non-self-peptides in the context of self-HLA have been found to harbor the potential to cross-react with peptides presented in the context of non-self HLA (25)(26)(27)(28).…”

Section: Introductionmentioning

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: Introductionmentioning

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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“…Variant changes could also influence CD4 T cell recognition (primary data, Supplementary Figs. [14][15][16][17]. In addition to loss of recognition of variant aa in B.1.1.7 (effects summarized in Table 1 and Figure 7) and/or P.1 lineages, we also noted strain-specific recognition of B.1.1.7associated sequences that were already prevalent in early 2020 and not unique to VBM (example, Supplementary Figure 10, indicated in blue).…”

Section: Recognition Of Sars-cov-2 Variants To Choose Variants For St...mentioning

confidence: 68%

T cell response to intact SARS-CoV-2 includes coronavirus cross-reactive and variant-specific components

Jing¹,

Wu²,

Krist³

et al. 2022

JCI Insight

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SARS-CoV-2 provokes a robust T cell response. Peptide-based studies exclude antigen processing and presentation biology and may influence T cell detection studies. To focus on responses to whole virus and complex antigens, we used intact SARS-CoV-2 and full-length proteins with dendritic cells (DC) to activate CD8 and CD4 T cells from convalescent persons. T cell receptor (TCR) sequencing showed partial repertoire preservation after expansion.Resultant CD8 T cells recognize SARS-CoV-2-infected respiratory tract cells, and CD4 T cells detect inactivated whole viral antigen. Specificity scans with proteome-covering protein/peptide arrays show that CD8 T cells are oligospecific per subject and that CD4 T cell breadth is higher. Some CD4 T cell lines enriched using SARS-CoV-2 cross-recognize whole seasonal coronavirus (sCoV) antigens, with protein, peptide, and HLA restriction validation. Conversely, recognition of some epitopes is eliminated for SARS-CoV-2 variants, including spike (S) epitopes in the alpha, beta, gamma, and delta variant lineages.

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“…TCRβ-sequences were identified using ARTISAN PCR adapted for TCR PCR(35, 36). Total mRNA was extracted from 190 pMHC-tetramer pos purified ( Supplementary Figure 1A ) virus-specific T-cell populations(37) using magnetic beads (Dynabead mRNA DIRECT kit; Invitrogen, Thermo Fisher Scientific). Ten μl (~1μg) of mRNA per sample was mixed with TCRβ constant region-specific primers (1μM final concentration) and SmartSeq2modified template-switching oligonucleotide (SS2m_TSO; 1μM final concentration) and denatured for 3 minutes at 72°C.…”

Section: Methodsmentioning

confidence: 99%

Public T-Cell Receptors (TCRs) Revisited by Analysis of the Magnitude of Identical and Highly-Similar TCRs in Virus-Specific T-Cell Repertoires of Healthy Individuals

Huisman

Hageman

Leboux

et al. 2021

Preprint

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Since multiple different T-cell receptor (TCR) sequences can bind to the same peptide-MHC combination and the number of TCR-sequences that can theoretically be generated even exceeds the number of T cells in a human body, the likelihood that many public identical (PUB-I) TCR-sequences frequently contribute to immune responses has been estimated to be low. Here, we quantitatively analyzed the TCR-repertoires of 190 purified virus-specific memory T-cell populations, directed against 21 antigens of Cytomegalovirus, Epstein-Barr virus and Adenovirus isolated from 29 healthy individuals, and determined the magnitude, defined as prevalence within the population and frequencies within individuals, of PUB-I TCR and of TCR-sequences that are highly-similar (PUB-HS) to these PUB-I TCR-sequences. We found that almost one third of all TCR nucleotide-sequences represented PUB-I TCR amino-acid (AA) sequences and found an additional 12% of PUB-HS TCRs differing by maximally 3 AAs. We illustrate that these PUB-I and PUB-HS TCRs were structurally related and contained shared core-sequences in their TCR-sequences. We found a prevalence of PUB-I and PUB-HS TCRs of up to 50% among individuals and showed frequencies of virus-specific PUB-I and PUB-HS TCRs making up more than 10% of each virus-specific T-cell population. These findings were confirmed by using an independent TCR-database of virus-specific TCRs. We therefore conclude that the magnitude of the contribution of PUB-I and PUB-HS TCRs to these virus-specific T-cell responses is high. Because the T cells from these virus-specific memory TCR-repertoires were the result of successful control of the virus in these healthy individuals, these PUB-HS TCRs and PUB-I TCRs may be attractive candidates for immunotherapy in immunocompromised patients that lack virus-specific T cells to control viral reactivation.Significance statementPublic T-cell responses, in which T cells expressing the same T-cell receptor (TCR) are found in different individuals, have been described. However, the magnitude of the contribution of these TCRs to immune responses, defined as prevalence within the population and frequencies within individuals, is not known. In this study we characterized and quantified public T-cell responses within virus-specific memory T cells of healthy individuals by determining identical and highly-similar TCRs recognizing the same antigen and sharing conserved CDR3 motifs. The magnitude of public T-cell responses was surprisingly high and we argue that these dominant TCRs with shared core-sequences could be utilized for diagnostic purposes and may provide attractive TCRs to be used for immunotherapy in immunocompromised patients.

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

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

T cell response to intact SARS-CoV-2 includes coronavirus cross-reactive and variant-specific components

Public T-Cell Receptors (TCRs) Revisited by Analysis of the Magnitude of Identical and Highly-Similar TCRs in Virus-Specific T-Cell Repertoires of Healthy Individuals

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