Understanding the connections between cellular metabolism, MHC class I regulation, and the immune response

Major histocompatibility complex (MHC) molecules are the core of vertebrates’ immune system, enabling the distinction between ‘self’ and ‘non-self’ or ‘missing-self’. MHC class I (MHCI) molecules are central to this function by regulating tolerance and rejection by cytotoxic CD8+ T cells and NK cells. Cellular metabolism, the ensemble of processes fulfilling the bioenergetic and biosynthetic needs of a cell, has been reported to influence MHCI expression in cancer cells. Unpublished data from my own laboratory reveal that an unappreciated correlation between metabolic perturbations and MHCI levels is observed also in non-transformed cells. Based on our preliminary results, we hypothesize that fluctuations in MHCI levels linked to metabolic states serve a twofold purpose. While conforming to the classic definition of ‘self’, metabolically abnormal cells can represent a threat for the organism. Fluctuations in MHCI expression might thus modulate the interaction with immune system cells, thereby favoring elimination of metabolically deregulated cells. At the same time, through their altered MHCI levels, cells exhibiting selected metabolic states might differently activate immune cells, thus impacting the host’s immunity as well. Therefore, this project aims to: 1) thoroughly define the correlations between selected metabolic perturbations and the expression of MHCI (but also of MHCI-related molecules, co-stimulatory, co-inhibitory, and NK cell ligands more broadly) in the cell subsets of interest; 2) uncover the underlying molecular mechanisms; and 3) determine the consequences of altered MHCI display on the immune response and towards metabolically abnormal cells in vitro and in vivo.