Research Papers:

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

Fiyaz Mohammed, Daniel H. Stones, Angela L. Zarling, Carrie R. Willcox, Jeffrey Shabanowitz, Kara L. Cummings, Donald F. Hunt, Mark Cobbold, Victor H. Engelhard and Benjamin E. Willcox _

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Oncotarget. 2017; 8:54160-54172. https://doi.org/10.18632/oncotarget.16952

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Fiyaz Mohammed1,*, Daniel H. Stones1,*, Angela L. Zarling2, Carrie R. Willcox1, Jeffrey Shabanowitz3, Kara L. Cummings2, Donald F. Hunt3, Mark Cobbold4,5,6, Victor H. Engelhard2 and Benjamin E. Willcox1

1Cancer Immunology and Immunotherapy Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

2Carter Immunology Center and Department of Microbiology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA

3Department of Chemistry, University of Virginia, Charlottesville, Virginia 22908, USA

4School of Immunity and Infection, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

5Current address: Cancer Centre, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

6Current address: Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129, USA

*These authors contributed equally to this work

Correspondence to:

Benjamin E. Willcox, email: [email protected]

Keywords: tumour immunology, phosphopeptide, peptide-MHC complex, neoepitope, peptide conformation

Received: February 17, 2017     Accepted: March 30, 2017     Published: April 08, 2017


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.

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