Antigen processing in the endoplasmic reticulum is monitored by semi-invariant αβ tcrs specific for a conserved peptide-qa-1b MHC class ib ligand

Ag processing in the endoplasmic reticulum (ER) by the ER aminopeptidase associated with Ag processing (ERAAP) is central to presentation of a normal peptide-MHC class I (MHC 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 Ag processing by responding to a highly conserved FL9 peptide that is presented by Qa-1b, a nonclassical MHC Ib molecule (QFL) in ERAAP-deficient cells. To understand the structural basis for recognition of the conserved ligand, we analyzed the ab TCRs of QFL-specific T cells. Individual cells in normal wild-type and TCRb-transgenic mice were assessed for QFL-specific TCR a-and b-chains. The QFL-specific cells expressed a predominant semi-invariant TCR generated by DNA rearrangement of TRAV9d-3-TRAJ21 a-chain and TRBV5-TRBD1-TRBJ2-7 b-chain gene segments. Furthermore, the CDR3 regions of the a-as well as b-chains were required for QFL ligand recognition. Thus, the ab TCRs used to recognize the peptide-Qa-1 ligand presented by ERAAP-deficient cells are semi-invariant and likely reflect a conserved mechanism for monitoring the fidelity of Ag processing in the ER.