Abstract
Proteins of the major histocompatibility complex (MHC) class I, or human leukocyte antigen (HLA) in humans interact with endogenous peptides and present them to T cell receptors (TCR), which in turn tune the immune system to recognize and discriminate between self and foreign (non-self) peptides. Of especial importance are peptides derived from tumor-associated antigens. T cells recognizing these peptides are found in cancer patients, but not in cancer-free individuals. What stimulates this recognition, which is vital for the success of checkpoint based therapy? A peptide derived from the protein p53 (residues 161–169 or p161) was reported to show this behavior. T cells recognizing this unmodified peptide could be further stimulated in vitro to create effective cancer killing CTLs (cytotoxic T lymphocytes). We hypothesize that the underlying difference may arise from post-translational glycosylation of p161 in normal individuals, likely masking it against recognition by TCR. Defects in glycosylation in cancer cells may allow the presentation of the native peptide. We investigate the structural consequences of such peptide glycosylation by investigating the associated structural dynamics.
Highlights
Major histocompatibility complex (MHC), or human leukocyte antigen in human (HLA) class I, belongs to a family of proteins that are found on the surfaces of cells and display endogenous peptides to T cell receptors (TCR) on cytotoxic T cells, resulting in the triggering of immune responses if the peptide displayed is recognized as a non-selfantigen [1]
The MHC class I or HLA class I proteins can be subdivided into three subtypes, namely HLA-A, HLA-B, and HLA-C, of which HLA-A24 is the most abundant allele in Asian and Caucasian populations [3]
This suggests that mutant p53 peptides can be presented on MHC class I receptors and recognized as non-self, resulting in recognition as a non-self-antigen by appropriate TCRs, culminating in the elimination of those cells [7]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. It is known that oncogenic mutations in p53 eliminate its tumor suppressor function, promote cell growth and proliferation, and inhibit apoptosis [6] This suggests that mutant p53 peptides can be presented on MHC class I receptors and recognized as non-self, resulting in recognition as a non-self-antigen by appropriate TCRs, culminating in the elimination of those cells [7]. Direct recognition of glycan from the glycopeptide, representing an immunodominant epitope of Sendai virus by TCRs of CD8+ cells, was revealed by combining crystallography and modeling [18] These studies suggest that glycosylation of epitopes can affect immune recognition, albeit in different ways. We investigate how p161 (in unglycosylated and glycosylated states) may be accommodated in the peptide presentation pocket of MHC class I and what the consequences of these binary complexes are on their interactions with TCR
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