Immune presentation and recognition of class I MHC phosphopeptide antigens

[摘要] Alterations to metabolic pathways, in particular post-translational modification, are a recognised hallmark of diseases such as autoimmunity, inflammation and cancer, and potentially provide a source of altered self antigens that can stimulate immune responses. Most notably, phosphorylated peptides have emerged as a group of tumour associated antigens which can be presented by MHC molecules and recognised by T-cells, and therefore represent promising candidates for future cancer immunotherapy strategies. However, how antigen phosphorylation impacts upon antigen presentation and recognition remains unclear. During this study I demonstrated that the phosphate moiety of phosphopeptides bearing the canonical P4 phosphorylation is more structurally diverse in its binding mode than previously thought. Strikingly, two epitopes exhibited a major conformational change upon addition of the phosphate moiety, effectively creating “conformational neoantigens”. This occurred through a similar mechanism for each epitope, whereby the presence of the phosphate moiety raised the position of the P4 Serine, allowing phosphate-mediated contacts with MHC residues and distorting the conformation of the central epitope region most critical for T- cell receptor recognition. Finally, I found that recognition of phosphopeptides can be both phosphate-dependent and epitope-specific at the level of the T-cell receptor. Therefore, this study shows that phosphorylation can have a profound and diverse effect on antigen binding, epitope identity and T-cell receptor recognition. In summary, my studies suggest that phosphopeptides are not only tumour associated but also highly antigenically distinct, establishing them as attractive candidates for cancer immunotherapy strategies.

[发布机构] University:University of Birmingham;Department:Institute of Cancer Studies

[关键词] R Medicine;RC Internal medicine;RC0254 Neoplasms. Tumors. Oncology (including Cancer)