Luimstra et al. describe a temperature-mediated peptide exchange method for generating many different epitope-specific MHC class I multimers in parallel. This simple and versatile technology allows fast and efficient production of MHC I reagents for immune monitoring of T cell responses.
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 epitopes 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.
Tumor-associated antigens (TAA) are monomorphic self-antigens that are proposed as targets for immunotherapeutic approaches to treat malignancies. We investigated whether T cells with sufficient avidity to recognize naturally overexpressed self-antigens in the context of self-HLA can be found in the T-cell repertoire of healthy donors. Minor histocompatibility antigen (MiHA)-specific T cells were used as model, as the influence of thymic selection on the T-cell repertoire directed against MiHA can be studied in both self (MiHApos donors)and non-self (MiHAneg donors) backgrounds. T-cell clones directed against the HLA*02:01-restricted MiHA HA-1H were isolated from HA-1Hneg/HLA-A*02:01pos and HA-1Hpos/HLA-A*02:01pos donors. Of the 16 unique HA-1H-specific T-cell clones, 5 T-cell clones derived from HA-1Hneg/HLA-A*02:01pos donors and 1 T-cell clone derived from an HA-1Hpos/HLA-A*02:01pos donor showed reactivity against HA-1Hpos target cells. Additionally, in total 663 T-cell clones (containing at least 91 unique clones expressing different T-cell receptors) directed against HLA*02:01-restricted peptides of TAA WT1-RMF, RHAMM-ILS, Proteinase-3-VLQ, PRAME-VLD and NY-eso-1-SLL were isolated from HLA-A*02:01pos donors. Only 3 PRAME-VLD- and 1 NY-eso-1-SLL-specific T-cell clone provoked IFN-gamma production and/or cytolysis upon stimulation with HLA-A*02:01pos malignant cell lines (but not primary malignant samples) naturally overexpressing the TAA. These results illustrate that self-HLA-restricted T cells specific for self-antigens like MiHA in MiHApos donors and TAA are present in peripheral blood of healthy individuals, but clinical efficacy would require highly effective in-vivo priming by peptide vaccination in the presence of proper adjuvants or in-vitro expansion of the low numbers of self-antigen-specific T cells of sufficient avidity to recognize endogenously processed antigen. T-cell clones directed against the HLA*02:01-restricted MiHA HA-1H were isolated from HA-1Hneg/HLA-A*02:01pos and HA-1Hpos/HLA-A*02:01pos donors. Of the 16 unique HA-1H-specific T-cell clones, 5 T-cell clones derived from HA-1Hneg/HLA-A*02:01pos donors and 1 T-cell clone derived from an HA-1Hpos/HLA-A*02:01pos donor showed reactivity against HA-1Hpos target cells. Additionally, in total 663 T-cell clones (containing at least 91 unique clones expressing different T-cell receptors) directed against HLA*02:01-restricted peptides of TAA WT1-RMF, RHAMM-ILS, Proteinase-3-VLQ, PRAME-VLD and NY-eso-1-SLL were isolated from HLA-A*02:01pos donors. Only 3 PRAME-VLD- and 1 NY-eso-1-SLL-specific T-cell clone provoked IFN-gamma production and/or cytolysis upon stimulation with HLA-A*02:01pos malignant cell lines (but not primary malignant samples) naturally overexpressing the TAA. These results illustrate that self-HLA-restricted T cells specific for self-antigens like MiHA in MiHApos donors and TAA are present in peripheral blood of healthy individuals, but clinical efficacy would require highly effective in-vivo priming by peptide vaccination in the presence of proper adjuvants or in-vitro expansion of the low numbers of self-antigen-specific T cells of sufficient avidity to recognize endogenously processed antigen.
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