The MHC-E peptide ligands for checkpoint CD94/NKG2A are governed by inflammatory signals, whereas LILRB1/2 receptors are peptide indifferent

• Published in: Cell reports (Cambridge) 2023-12, Vol.42 (12), p.113516-113516, Article 113516
• Main Authors: Middelburg, Jim, Ghaffari, Soroush, Schoufour, Tom A.W., Sluijter, Marjolein, Schaap, Gaby, Göynük, Büsra, Sala, Benedetta M., Al-Tamimi, Lejla, Scheeren, Ferenc, Franken, Kees L.M.C., Akkermans, Jimmy J.L.L., Cabukusta, Birol, Joosten, Simone A., Derksen, Ian, Neefjes, Jacques, van der Burg, Sjoerd H., Achour, Adnane, Wijdeven, Ruud H.M., Weidanz, Jon, van Hall, Thorbald
• Format: Article
• Language: English
• Subjects: Animals; CP: Cancer; CP: Immunology; Histocompatibility Antigens Class I - metabolism; immune checkpoint; immunotherapy of cancer; inflammation; interferon; Killer Cells, Natural; Leukocyte Immunoglobulin-like Receptor B1 - metabolism; Ligands; LILRB1; Medicin och hälsovetenskap; MHC-E; Mice; Neoplasms - metabolism; NK Cell Lectin-Like Receptor Subfamily C - metabolism; NKG2A; peptide-loading complex; Peptides - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113516

The immune checkpoint NKG2A/CD94 is a promising target for cancer immunotherapy, and its ligand major histocompatibility complex E (MHC-E) is frequently upregulated in cancer. NKG2A/CD94-mediated inhibition of lymphocytes depends on the presence of specific leader peptides in MHC-E, but when and where they are presented in situ is unknown. We apply a nanobody specific for the Qdm/Qa-1b complex, the NKG2A/CD94 ligand in mouse, and find that presentation of Qdm peptide depends on every member of the endoplasmic reticulum-resident peptide loading complex. With a turnover rate of 30 min, the Qdm peptide reflects antigen processing capacity in real time. Remarkably, Qdm/Qa-1b complexes require inflammatory signals for surface expression in situ, despite the broad presence of Qa-1b molecules in homeostasis. Furthermore, we identify LILRB1 as a functional inhibition receptor for MHC-E in steady state. These data provide a molecular understanding of NKG2A blockade in immunotherapy and assign MHC-E as a convergent ligand for multiple immune checkpoints. [Display omitted] •A novel antibody selectively binds to mouse MHC-E (Qa-1b) with Qdm leader peptide•Qdm peptide presentation requires inflammatory signals and the full peptide-loading complex•Inhibitory LILRB1/2 receptors engage human MHC-E (HLA-E) irrespective of peptide cargo Middelburg et al. show that the non-classical MHC-E is a central checkpoint ligand for inhibitory receptors on myeloid and lymphoid immunocytes. The LILRB1/2 receptors interact with MHC-E irrespective of the peptide cargo, but the presentation of particular leader peptides, required for CD94/NKG2A interaction, is induced by inflammation.