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

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Middelburg J, Ghaffari S, Schoufour TAW, Sluijter M, Schaap G, Göynük B, Sala BM, Al-Tamimi L, Scheeren F, Franken KLMC, Akkermans JJLL, Cabukusta B, Joosten SA, Derksen I, Neefjes J, van der Burg SH, Achour A, Wijdeven RHM, Weidanz J, van Hall T

Cell Reports 42 (12) 113516 [2023-12-26; online 2023-12-03]

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.

PubMed 38048225

DOI 10.1016/j.celrep.2023.113516

Crossref 10.1016/j.celrep.2023.113516

pii: S2211-1247(23)01528-0