The murine MHC-E molecule Qa-1b is surface displayed in a peptide-free conformation in homeostasis

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Qa-1 b , the murine ortholog of the nonclassical MHC-E family, contains minimal polymorphism and exhibits reduced surface stability compared with classical MHC class I molecules. To investigate Qa-1 b conformations and their immunological relevance, we employed two antibodies: EXX-1, which selectively recognizes Qa-1 b bound to the canonical leader peptide Qdm, and 6A8.6F10, a broadly used Qa-1 b -reactive antibody. Genome-wide CRISPR screens revealed that Qdm presentation was induced by interferon-γ and required the components of the peptide-loading complex (PLC) and endoplasmic reticulum quality control. EXX-1 binding thus reflected broad cellular integrity and mirrored CD94/NKG2x receptor engagement. In contrast, 6A8.6F10 staining occurred independently of PLC components such as ERAP1 and tapasin, and intriguingly increased in their absence. Accordingly, exogenous pulsing with Qa-1 b -binding peptides markedly reduced 6A8.6F10 antibody binding and resonance shift assays revealed that 6A8.6F10 selectively recognizes peptide-deficient Qa-1 b complexes. These findings suggest an additional layer of regulation beyond the immune checkpoint NKG2x/CD94, involving peptide-free MHC-E.

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