The antigenic identity of human class I MHC phosphopeptides is critically dependent upon phosphorylation status

Mohammed, Fiyaz, Stones, Daniel H ORCID: 0000-0002-8981-7943, Zarling, Angela L., Willcox, Carrie R., Shabanowitz, Jeffrey, Cummings, Kara L., Hunt, Donald F., Cobbold, Mark, Engelhard, Victor H. and Willcox, Benjamin E. (2017) The antigenic identity of human class I MHC phosphopeptides is critically dependent upon phosphorylation status. Oncotarget, 8 (33). pp. 54160-54172. doi:10.18632/oncotarget.16952

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Dysregulated post-translational modification provides a source of altered self-antigens that can stimulate immune responses in autoimmunity, inflammation, and cancer. In recent years, phosphorylated peptides have emerged as a group of tumour-associated antigens presented by MHC molecules and recognised by T cells, and represent promising candidates for cancer immunotherapy. However, the impact of phosphorylation on the antigenic identity of phosphopeptide epitopes is unclear. Here we examined this by determining structures of MHC-bound phosphopeptides bearing canonical position 4-phosphorylations in the presence and absence of their phosphate moiety, and examining phosphopeptide recognition by the T cell receptor (TCR). Strikingly, two peptides exhibited major conformational changes upon phosphorylation, involving a similar molecular mechanism, which focussed changes on the central peptide region most critical for T cell recognition. In contrast, a third epitope displayed little conformational alteration upon phosphorylation. In addition, binding studies demonstrated TCR interaction with an MHC-bound phosphopeptide was both epitope-specific and absolutely dependent upon phosphorylation status. These results highlight the critical influence of phosphorylation on the antigenic identity of naturally processed class I MHC epitopes. In doing so they provide a molecular framework for understanding phosphopeptide-specific immune responses, and have implications for the development of phosphopeptide antigen-specific cancer immunotherapy approaches.

Item Type: Article
Article Type: Article
Uncontrolled Keywords: Tumour immunology; Phosphopeptide; Peptide-MHC complex; Neoepitope; Peptide conformation
Subjects: Q Science > QR Microbiology
Divisions: Schools and Research Institutes > School of Education and Science
Research Priority Areas: Place, Environment and Community
Depositing User: Daniel Stones
Date Deposited: 09 Oct 2018 11:00
Last Modified: 01 Sep 2023 15:33

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