MHC Class I Presentation is limited by the Availability of “Empty” MHC Molecules Rather than by the Supply of Peptide Ligands

Introduction

While antigen processing and presentation by the major histocompatibility complex class I (MHC‐I) molecules have been extensively studied, a question arises as to whether the MHC‐I presentation level is limited by the availability of peptide ligands within the ER or by the supply of peptide-receptive (empty) MHC molecules.

Martial and method

This study clarifies this issue by inducing major perturbations and competition for ligands for MHC‐I presentation in human breast cancer cells. First, the MCF-7 cultured cells were treated with interferons. In addition, untreated cells were transfected with recombinant soluble MHC molecules that compete with the endogenous membranal MHC molecules for peptide loading.

Results and discussion

Treatment with interferons led to elevated presentation levels of the MHC-B molecules with their bound peptidome, relative to the MHC-A and MHC-C molecules of the cells. Since all of the MHC allotypes of the MCF-7 cell line present peptides with similar molecular properties, the interferon treatments were expected to have similar effect on all of the MHC allotypes, a phenomenon that was not observed. To further investigate the issue, high expression levels of recombinant soluble MHC-A were induced in the cells, to create a competition for peptides ligands between the soluble and the identical endogenous membranal MHC-A. This competition did not affect the membranal MHC-A presentation levels or its bound peptidome.

Conclusion

These results suggest that in contrary to the common opinion, the MHC presentation levels are limited by the availability of peptide-receptive molecules rather than by the supply of peptide ligands. These findings are important for the basic understanding of the antigen processing and presentation pathway, as well as vaccines design for pathogens infections and cancer immunotherapy.