{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:12:51Z","timestamp":1790813571937,"version":"4.1.0"},"reference-count":87,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,6,19]],"date-time":"2020-06-19T00:00:00Z","timestamp":1592524800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Natural killer (NK) cell therapies are a tool to antagonize a dysfunctional immune system. NK cells recognize malignant cells, traffic to a tumor location, and infiltrate the solid tumor. The immune checkpoint molecule human leukocyte antigen (HLA)-G is upregulated on malignant cells but not on healthy surrounding cells, the requirement of understanding the basis of receptor mediated events at the HLA-G\/NK cell interface becomes obvious. The NK cell receptors ILT2 and KIR2DL4 have been described to bind to HLA-G; however, their differential function and expression levels on NK cell subsets suggest the existence of an unreported receptor. Here, we performed a ligand-based receptor capture on living cells utilizing sHLA-G*01:01 molecules coupled to TriCEPS and bound to NK cells followed by mass spectrometric analyses. We could define NKG2A\/CD94 as a cognate receptor of HLA-G. To verify the results, we used the reciprocal method by expressing recombinant soluble heterodimeric NKG2A\/CD94 molecules and used them to target HLA-G*01:01 expressing cells. NKG2A\/CD94 could be confirmed as an immune receptor of HLA-G*01:01. Despite HLA-G is marginal polymorphic, we could previously demonstrate that the most common allelic subtypes HLA-G*01:01\/01:03 and 01:04 differ in peptide repertoire, their engagement to NK cells, their catalyzation of dNK cell proliferation and their impact on NK cell development. Continuing these studies with regard to NKG2A\/CD94 engagement we engineered recombinant single antigen presenting K562 cells and targeted the surface expressed HLA-G*01:01, 01:03 or 01:04 molecules with NKG2A\/CD94. Specificity and sensitivity of HLA-G*01:04\/NKG2A\/CD94 engagement could be significantly verified. The binding affinity decreases when using K562-G*01:03 or K562-G*01:01 cells as targets. These results demonstrate that the ligand-receptor assignment between HLA-G and NKG2A\/CD94 is dependent of the amino acid composition in the HLA-G heavy chain. Understanding the biophysical basis of receptor-mediated events that lead to NK cell inhibition would help to remove non-tumor reactive cells and support personalized mild autologous NK cell therapies.<\/jats:p>","DOI":"10.3390\/ijms21124362","type":"journal-article","created":{"date-parts":[[2020,6,19]],"date-time":"2020-06-19T10:43:58Z","timestamp":1592563438000},"page":"4362","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["NKG2A\/CD94 Is a New Immune Receptor for HLA-G and Distinguishes Amino Acid Differences in the HLA-G Heavy Chain"],"prefix":"10.3390","volume":"21","author":[{"given":"Gia-Gia T.","family":"H\u00f2","sequence":"first","affiliation":[{"name":"Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander A.","family":"Celik","sequence":"additional","affiliation":[{"name":"Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor","family":"Huyton","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Biophysical Chemistry, 37077 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiebke","family":"Hiemisch","sequence":"additional","affiliation":[{"name":"Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3875-3190","authenticated-orcid":false,"given":"Rainer","family":"Blasczyk","sequence":"additional","affiliation":[{"name":"Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwendolin S.","family":"Simper","sequence":"additional","affiliation":[{"name":"Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5826-1989","authenticated-orcid":false,"given":"Christina","family":"Bade-Doeding","sequence":"additional","affiliation":[{"name":"Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1126\/science.2326636","article-title":"A class I antigen, HLA-G, expressed in human trophoblasts","volume":"248","author":"Kovats","year":"1990","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1096\/fj.04-2078rev","article-title":"HLA-G and immune tolerance in pregnancy","volume":"19","author":"Hunt","year":"2005","journal-title":"FASEB J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/j.ajog.2004.01.033","article-title":"HLA-G protein concentrations in maternal serum and placental tissue are decreased in preeclampsia","volume":"191","author":"Yie","year":"2004","journal-title":"Am. 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