How antigen-processing proteins shape immunity

In diseases such as cancer or infection, the body’s process of presenting peptides through the antigen-processing and presentation machinery, or APPM, to immune cells is often altered. A subset of molecules called human leukocyte antigen class I, or HLA-I, presents these peptides to immune cells, constituting what is known as the immunopeptidome, which is critical for immune surveillance. However, scientists have yet to fully understand how individual components of the APPM influence the composition and diversity of the immunopeptidome.

T-cell receptor in complex with the MHC class II-peptide complex. The antigen (light green) is a peptide from a tumor cell, bacteria or virus.

Ilja Shapiro and a team of researchers based in Switzerland and the Netherlands published a study in Molecular & Cellular Proteomics where they knocked out 11 genes involved in the APPM in a cell line model to assess how these perturbations shape the immunopeptidomic landscape. They found that deleting the CALR gene had minor effects on reducing immunopeptidome diversity, while, as expected, deleting B2M led to a dramatic change in the immunopeptidome. More specifically, deleting genes such as TAP1, TAP2, or IRF2 caused a significant change in the length preference, binding affinity, diversity and presentation capacity on HLA-I molecules. These results highlight the importance of the APPM in regulating immunity and may help explain how defects in antigen presentation reshape the immunopeptidome in diseases such as cancer. Future research can help develop predictive tools to investigate HLA-bound peptides when presentation defects arise in diseases.