The MHC-E peptide ligands for checkpoint CD94/NKG2A are governed by inflammatory signals, whereas LILRB1/2 receptors are peptide indifferent
Jim Middelburg, Soroush Ghaffari, Tom A. W. Schoufour, Marjolein Sluijter, Gaby Schaap, Büşra Göynük, Benedetta Maria Sala, Lejla Al-Tamimi, Ferenc A. Scheeren, Kees L. M. C. Franken, Jimmy J.L.L. Akkermans, Birol Cabukusta, Simone A. Joosten, Ian Derksen, Jacques Neefjes, Sjoerd H. van der Burg, Adnane Achour, Ruud H. Wijdeven, Jon A. Weidanz, Thorbald van Hall
Abstract
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-1 b 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-1 b complexes require inflammatory signals for surface expression in situ , despite the broad presence of Qa-1 b 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.