Antigen presentation of post-translationally modified peptides in major histocompatibility complexes

T cells of the adaptive immune system recognize pathogens and malignantly transformed cells through a process called antigen presentation. During this process, peptides are displayed on major histocompatibility complex (MHC) class I and II molecules. Self-reactive T cells are typically removed or suppressed during T-cell development and through peripheral tolerance mechanisms, ensuring that only T cells recognizing peptides that are either absent or present in low abundance under normal conditions remain. This selective process allows T cells to respond to peptides derived from foreign proteins while ignoring those from self-proteins. However, T cells can also respond to peptides derived from proteins that have undergone post-translational modifications (PTMs). Over 200 different PTMs have been described, and while they are essential for protein function, localization and stability, their dysregulation is often associated with disease conditions. PTMs can affect the proteolytic processing of proteins and prevent MHC binding, thereby changing the repertoire of peptides presented on MHC molecules. However, it is also increasingly evident that many peptides presented on MHC molecules carry PTMs, which can alter their immunogenicity. As a result, the presentation of post-translationally modified peptides by MHC molecules plays a significant role in various diseases, as well as autoimmune disorders and allergies. This review will provide an overview of the impact of PTMs on antigen presentation and their implications for immune recognition and disease.