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

TL;DR

Mouse T cells that recognize MHC-E can develop using non-specific MHC interactions, revealing new insights into their thymic development.

Contribution

The study reveals that non-cognate CD8-MHC I interactions are essential for the development of MHC-E-restricted T cells.

Findings

QFL T cells can develop without the Qa1b molecule but require classical MHC Ia or H2-T11.

Non-cognate CD8-MHC Ia interactions enhance responses to MHC Ib ligands in QFL thymocytes.

H2-T11 is identified as an alternative ligand for QFL TCR.

Abstract

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.

Mouse Qa1b‐restricted T cells show promiscuous requirements for positive selection. Using in vivo tetramer enrichment, in vitro APC engineering, and in vitro thymocyte stimulation, we demonstrate that a Qa1b‐restricted T cell population can be selected by both Qa1b and H2‐T11, and depends on non‐cognate CD8‐MHC I binding.

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