Discovery of conserved peptide-MHC epitopes for directly alloreactive CD8+ T cells
Mass Spectrometry allied with in-vivo generation of activated alloreactive T cell populations and tetramer screening facilitates the identification of endogenous peptides that are directly recognised in complex with allogeneic Major Histocompatibility class I (MHC I) molecules by alloreactive CD8+ T...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Transplantation |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/frtra.2025.1525003/full |
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| author | Alexandra E. Hill Eric T. Son Moumita Paul-Heng Chuanmin Wang Shivanjali Ratnaseelan Martina Denkova Pouya Faridi Asolina Braun Anthony W. Purcell Nicole A. Mifsud Alexandra F. Sharland |
| author_facet | Alexandra E. Hill Eric T. Son Moumita Paul-Heng Chuanmin Wang Shivanjali Ratnaseelan Martina Denkova Pouya Faridi Asolina Braun Anthony W. Purcell Nicole A. Mifsud Alexandra F. Sharland |
| author_sort | Alexandra E. Hill |
| collection | DOAJ |
| description | Mass Spectrometry allied with in-vivo generation of activated alloreactive T cell populations and tetramer screening facilitates the identification of endogenous peptides that are directly recognised in complex with allogeneic Major Histocompatibility class I (MHC I) molecules by alloreactive CD8+ T cells. We had previously used this approach for the discovery of immunogenic self-peptides presented by the allomorph H-2Kb (Kb). In this study, we identified 22 highly immunogenic self-peptides presented by H-2Kd (Kd). Peptide abundance across skin, spleen and liver samples (estimated as the product of the spectral intensity obtained for these samples) was the principal factor influencing recognition of peptide-Kd epitopes. Predicted binding affinity (BA score) and overall peptide hydrophobicity were also independently correlated with immunogenicity, while there was no significant correlation between the IEDB immunogenicity score and the proportion of T cells recognising a given epitope. Eight peptide-Kd epitopes were selected for inclusion in a tetramer panel to detect directly alloreactive CD8+ T cells. This panel bound over 30% of activated alloreactive CD8+ T cells after a prime-boost against Kd. Moreover, the panel identified alloreactive CD8+ T cells within the graft infiltrate, spleen and draining lymph node during rejection of a Kd-bearing heart graft. In conclusion, small animal studies have demonstrated the feasibility of high-throughput approaches for the discovery of pMHC epitopes recognised by directly alloreactive T cells. Translating this approach to the human setting is achievable and will yield both critical insights into the fundamental basis of alloreactivity and powerful tools for immune monitoring in transplantation. |
| format | Article |
| id | doaj-art-4efabd470f954a5dae2432bd685cbf28 |
| institution | Kabale University |
| issn | 2813-2440 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Transplantation |
| spelling | doaj-art-4efabd470f954a5dae2432bd685cbf282025-01-29T06:46:18ZengFrontiers Media S.A.Frontiers in Transplantation2813-24402025-01-01410.3389/frtra.2025.15250031525003Discovery of conserved peptide-MHC epitopes for directly alloreactive CD8+ T cellsAlexandra E. Hill0Eric T. Son1Moumita Paul-Heng2Chuanmin Wang3Shivanjali Ratnaseelan4Martina Denkova5Pouya Faridi6Asolina Braun7Anthony W. Purcell8Nicole A. Mifsud9Alexandra F. Sharland10Transplantation Immunobiology Group, Sydney Medical School, University of Sydney Faculty of Medicine and Health, Sydney, NSW, AustraliaTransplantation Immunobiology Group, Sydney Medical School, University of Sydney Faculty of Medicine and Health, Sydney, NSW, AustraliaTransplantation Immunobiology Group, Sydney Medical School, University of Sydney Faculty of Medicine and Health, Sydney, NSW, AustraliaTransplantation Immunobiology Group, Sydney Medical School, University of Sydney Faculty of Medicine and Health, Sydney, NSW, AustraliaTransplantation Immunobiology Group, Sydney Medical School, University of Sydney Faculty of Medicine and Health, Sydney, NSW, AustraliaTransplantation Immunobiology Group, Sydney Medical School, University of Sydney Faculty of Medicine and Health, Sydney, NSW, AustraliaDepartment of Biochemistry and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, AustraliaDepartment of Biochemistry and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, AustraliaDepartment of Biochemistry and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, AustraliaDepartment of Biochemistry and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, AustraliaTransplantation Immunobiology Group, Sydney Medical School, University of Sydney Faculty of Medicine and Health, Sydney, NSW, AustraliaMass Spectrometry allied with in-vivo generation of activated alloreactive T cell populations and tetramer screening facilitates the identification of endogenous peptides that are directly recognised in complex with allogeneic Major Histocompatibility class I (MHC I) molecules by alloreactive CD8+ T cells. We had previously used this approach for the discovery of immunogenic self-peptides presented by the allomorph H-2Kb (Kb). In this study, we identified 22 highly immunogenic self-peptides presented by H-2Kd (Kd). Peptide abundance across skin, spleen and liver samples (estimated as the product of the spectral intensity obtained for these samples) was the principal factor influencing recognition of peptide-Kd epitopes. Predicted binding affinity (BA score) and overall peptide hydrophobicity were also independently correlated with immunogenicity, while there was no significant correlation between the IEDB immunogenicity score and the proportion of T cells recognising a given epitope. Eight peptide-Kd epitopes were selected for inclusion in a tetramer panel to detect directly alloreactive CD8+ T cells. This panel bound over 30% of activated alloreactive CD8+ T cells after a prime-boost against Kd. Moreover, the panel identified alloreactive CD8+ T cells within the graft infiltrate, spleen and draining lymph node during rejection of a Kd-bearing heart graft. In conclusion, small animal studies have demonstrated the feasibility of high-throughput approaches for the discovery of pMHC epitopes recognised by directly alloreactive T cells. Translating this approach to the human setting is achievable and will yield both critical insights into the fundamental basis of alloreactivity and powerful tools for immune monitoring in transplantation.https://www.frontiersin.org/articles/10.3389/frtra.2025.1525003/fullallorecognitionpeptide-MHCCD8+ T cellepitope discoveryheart transplantacute rejection |
| spellingShingle | Alexandra E. Hill Eric T. Son Moumita Paul-Heng Chuanmin Wang Shivanjali Ratnaseelan Martina Denkova Pouya Faridi Asolina Braun Anthony W. Purcell Nicole A. Mifsud Alexandra F. Sharland Discovery of conserved peptide-MHC epitopes for directly alloreactive CD8+ T cells Frontiers in Transplantation allorecognition peptide-MHC CD8+ T cell epitope discovery heart transplant acute rejection |
| title | Discovery of conserved peptide-MHC epitopes for directly alloreactive CD8+ T cells |
| title_full | Discovery of conserved peptide-MHC epitopes for directly alloreactive CD8+ T cells |
| title_fullStr | Discovery of conserved peptide-MHC epitopes for directly alloreactive CD8+ T cells |
| title_full_unstemmed | Discovery of conserved peptide-MHC epitopes for directly alloreactive CD8+ T cells |
| title_short | Discovery of conserved peptide-MHC epitopes for directly alloreactive CD8+ T cells |
| title_sort | discovery of conserved peptide mhc epitopes for directly alloreactive cd8 t cells |
| topic | allorecognition peptide-MHC CD8+ T cell epitope discovery heart transplant acute rejection |
| url | https://www.frontiersin.org/articles/10.3389/frtra.2025.1525003/full |
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