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 (Qa1b) 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 Qa1b molecule, their development was abrogated in the combined absence of classical MHC Ia and Qa1b. 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 Qa1b-specific T cell population.