Non-cognate CD8 Binding to MHC I Promotes Positive Selection of an MHC-E Restricted CD8 T Cell Population

MHC-E-restricted CD8 T cells are emerging as an attractive therapeutic mechanism due to their strong protective capacity and ability to respond to cells with defects in antigen processing; however, their thymic development remains poorly understood. Here, we explore the MHC ligand requirement for thymic development of T cells reactive to a self-peptide (FL9) presented by mouse MHC-E (Qa1^b) under conditions of deficiency in the endoplasmic reticulum aminopeptidase associated with antigen processing (ERAAP), called QFL T cells. We show that, while QFL T cells can develop in the absence of the restricting Qa1^b molecule, their development was abrogated in the combined absence of classical MHC Ia and Qa1^b. Interestingly, QFL thymocytes did not recognize classical MHC Ia molecules through their TCR but instead used non-cognate CD8-MHC Ia interactions to boost responses to MHC Ib ligands. Furthermore, we also identify an alternative ligand for the QFL TCR, the MHC Ib molecule H2-T11. Our data provide evidence that both cognate and non-cognate MHC interactions contribute to the development of a Qa1^b-specific T cell population.