| First Author | Middelburg J | Year | 2023 |
| Journal | Cell Rep | Volume | 42 |
| Issue | 12 | Pages | 113516 |
| PubMed ID | 38048225 | Mgi Jnum | J:349488 |
| Mgi Id | MGI:7570039 | Doi | 10.1016/j.celrep.2023.113516 |
| Citation | Middelburg J, et al. (2023) The MHC-E peptide ligands for checkpoint CD94/NKG2A are governed by inflammatory signals, whereas LILRB1/2 receptors are peptide indifferent. Cell Rep 42(12):113516 |
| abstractText | 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. |
