Antigen processing in the endoplasmic reticulum (ER) by ERAAP, the ER aminopeptidase associated with antigen processing is central to presentation of a normal peptide-MHC class I repertoire. Alternations in ERAAP function cause dramatic changes in the MHC I presented peptides which elicit potent immune responses. An unusual subset of CD8+ T cells monitor normal antigen processing by responding to a highly conserved FL9 peptide that is presented by Qa-1b, a non-classical MHC Ib molecule (QFL) in ERAAP-deficient cells. To understand the structural basis for recognition of the conserved ligand, we analyzed the αβ TCRs of QFL-specific T cells. Individual cells in normal wild-type and TCR β transgenic mice were assessed for QFL-specific TCR α-and β-chains. The QFL-specific cells expressed a predominant semi-invariant TCR generated by DNA rearrangement of TRAV9d-3-TRAJ21 alpha and TRBV5-TRBD1-TRBJ2-7 beta chain gene segments. Further, the CDR3 regions of the α as well as β chains were required for QFL ligand recognition. Thus, the αβ TCRs used to recognize the peptide-Qa-1 ligand presented by ERAAP-deficient cells are semi-invariant and likely reflect conserved mechanism for monitoring the fidelity of antigen processing in the ER.

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