Impact of Post-Translational Modification on MHC Peptide Binding and TCR Engagement

Abstract The human major histocompatibility complex (MHC) plays a crucial role in the presentation of peptidic fragments from proteins; these peptides can be derived from self-proteins or from non-human antigens, such as those produced by viruses or bacteria. To prevent cytotoxicity against healthy cells, thymocytes expressing T cell receptors (TCRs) that recognize self-peptides are removed from circulation in a process called negative selection. However, post-translational modifications (PTMs) are largely excluded from negative selection; this feature opens the door to the possibility that PTMs directly contribute to the development of autoreactive T cells and subsequent autoimmune diseases. Despite it being well-established that PTMs are prevalent in peptides presented on MHCs, the exact mechanisms by which PTMs influence the antigen presentation machinery remains poorly understood. In our work, we introduce chemical modifications mirroring PTMs onto peptides to systematically investigate their impact on MHC binding and TCR recognition. Our findings reveal the numerous ways PTMs alter antigen presentation, which could have implications for tumor neoantigen presentation.