The MHC I immunopeptidome conveys to the cell surface an integrative view of cellular regulation

Abstract

• Using a quantitative high-throughput mass spectrometry-based approach, we found that inhibition of the mammalian target of rapamycin (mTOR) results in dynamic changes in the composition of the MHC I immunopeptidome.

• We provide systems-level evidence that the MHC I immunopeptidome projects at the cell surface a representation of biochemical networks and metabolic events regulated at multiple levels (transcriptional and co- or post-translational level) inside the cell.

• We demonstrate that the composition of the MHC I immunopeptidome changes in response to metabolic perturbations and we provide insights into how mammalian cells communicate their metabolic status to the adaptive immune system.

Abstract

Self/non-self discrimination is a fundamental requirement of life. Endogenous peptides presented by major histocompatibility complex class I (MHC I) molecules represent the essence of self for CD8 T lymphocytes. These MHC I peptides (MIPs) are collectively referred to as the immunopeptidome. From a systems-level perspective, very little is known about the origin, composition and plasticity of the immunopeptidome. Here, we show that the immunopeptidome, and therefore the nature of the immune self, is plastic and moulded by cellular metabolic activity. By using a quantitative high-throughput mass spectrometry-based approach, we found that altering cellular metabolism via the inhibition of the mammalian target of rapamycin results in dynamic changes in the cell surface MIPs landscape. Moreover, we provide systems-level evidence that the immunopeptidome projects at the cell surface a representation of biochemical networks and metabolic events regulated at multiple levels inside the cell. Our findings open up new perspectives in systems immunology and predictive biology. Indeed, predicting variations in the immunopeptidome in response to cell-intrinsic and -extrinsic factors could be relevant to the rational design of immunotherapeutic interventions.