Self-reactive T cells restricted by non-classical MHC Ib are associated with metabolic disease

Abstract

Abstract The normal peptide repertoire presented by classical and non-classical MHC class I molecules is regulated by ERAAP, the ER aminopeptidase associated with antigen processing. Loss of ERAAP’s peptide trimming function in cells causes dramatic changes in the peptide repertoire. The changes in the peptide repertoire enhance the immunogenicity of ERAAP-deficient cells and elicit potent immune responses in otherwise syngeneic wild-type mice. Normal ERAAP function is monitored by an unusual subset of semi-invariant CD8+ T cells that recognize the QFL ligand. The QFL ligand consists of a peptide encoded by the highly conserved FAM49a/b genes that is presented by Qa-1b, a non-classical MHC Ib molecule only on surface of ERAAP-deficient cells. We show that these QFL-specific CD8+ T cells (QFL-T cells) bear unique and semi-invariant αβ TCRs. Genetic manipulation of the expression of the self-QFL ligand and functional characteristics of QFL-T cells shows that in addition to monitoring ERAAP function, QFL-T cells may also regulate metabolic activity.