Antigen Processing in the Endoplasmic Reticulum Is Monitored by Semi-Invariant αβ TCRs Specific for a Conserved Peptide–Qa-1b MHC Class Ib Ligand

Abstract

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.

T Cells Engaging the Conserved MHC Class Ib Molecule Qa-1b with TAP-Independent Peptides Are Semi-Invariant Lymphocytes

“…However, classical markers of “agonist selection,” like CD44 and CD25, were not enhanced, and the overall phenotype was much less convincing compared to real invariant T cell subsets and closer resembled the pattern of conventional T cells. Our findings corroborate those reported for Qa-1 b -restricted T cells targeting ERAAP-deficient targets ( 26 , 32 ).…”

“…Thus, the TCR usage of these three Qa-1 b -restricted T cell clones was generally diverse, but conserved in the Vα segment. Interestingly, limited TCR Vα diversity was recently also described for Qa-1 b -restricted T lymphocytes specific for ERAAP-deficient target cells, although another Vα usage was reported for these CD8 + T cells ( 32 ).…”

“…The Qa-1 b T cell population we describe here are clearly distinct from these T cell subsets, as both TCRα and TCRβ chains harbor much more diversity and, additionally, a diverse set of peptide epitopes are recognized (see Figure 1 ). Recently, a very restricted usage of only TCRα chains was observed in a TCRβ-transgenic mouse with specificity for a Qa-1 b -presented peptide was reported ( 32 ). Though the Vα element in that study was not the same as we found, together, these findings indicate that the monomorphic Qa-1 b molecule, normally presenting the dominant Qdm peptide in homeostasis ( 4 ) imposes a strong limitation to the pool of functional TCRs that engage this MHC class Ib molecule during the selection process.…”

Casting a wider net: Immunosurveillance by nonclassical MHC molecules

“…This peptide is only presented in cells lacking ERAP activity. Qa-1–specific T cells are present in nonimmunized mice in relatively large numbers and with memory markers, suggesting their constitutive activation [16]. They might play a critical role in immunity to herpesviruses, which are known to down-regulate ERAP [17] but likely have additional function as well, because laboratory mice are generally free of herpesvirus infections.…”

Mobilizing unconventional T cells

“…Another avenue for further investigation is the diversity of the TCR repertoire for HLA-E–presented ligands. For HLA-E–CMV peptides, preferential usage of the TCR β-chain variable region (Vβ16) has been reported, and mouse tumor models suggest a role for semi-invariant TCRαβ in recognizing certain self-peptides bound to Qa-1 (12, 13). An unanswered question is whether HLA-E–restricted unconventional T cells display narrow TCR repertories similar to those in the mouse, or broader TCR repetoires, and whether these differ according to disease.…”