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non-classical class Ib molecule human leukocyte antigen E (HLA-E) has limited polymorphism and can bind HLA class Ia leader peptides (VL9). HLA-E-VL9 complexes interact with the natural killer (NK) cell receptors NKG2A-C/CD94 and regulate NK cell-mediated cytotoxicity. Here we report the isolation of 3H4, a murine HLA-E-VL9-specific IgM antibody that enhances killing of HLA-E-VL9-expressing cells by an NKG2A<sup>+</sup> NK cell line. Structural analysis reveal that 3H4 acts by preventing CD94/NKG2A docking on HLA-E-VL9. Upon in vitro maturation, an affinity-optimized IgG form of 3H4 showes enhanced NK killing of HLA-E-VL9-expressing cells. HLA-E-VL9-specific IgM antibodies similar in function to 3H4 are also isolated from na\u00efve B cells of cytomegalovirus (CMV)-negative, healthy humans. Thus, HLA-E-VL9-targeting mouse and human antibodies isolated from the na\u00efve B cell antibody pool have the capacity to enhance NK cell cytotoxicity.","bibjson":{"author":[{"initials":"D","lastname":"Li","name":"Li D"},{"initials":"S","lastname":"Brackenridge","name":"Brackenridge S"},{"initials":"LC","lastname":"Walters","name":"Walters LC"},{"initials":"O","lastname":"Swanson","name":"Swanson O"},{"initials":"K","lastname":"Harlos","name":"Harlos K"},{"initials":"D","lastname":"Rozbesky","name":"Rozbesky D"},{"initials":"DW","lastname":"Cain","name":"Cain DW"},{"initials":"K","lastname":"Wiehe","name":"Wiehe K"},{"initials":"RM","lastname":"Scearce","name":"Scearce RM"},{"initials":"M","lastname":"Barr","name":"Barr M"},{"initials":"Z","lastname":"Mu","name":"Mu Z"},{"initials":"R","lastname":"Parks","name":"Parks R"},{"initials":"M","lastname":"Quastel","name":"Quastel M"},{"initials":"RJ","lastname":"Edwards","name":"Edwards RJ"},{"initials":"Y","lastname":"Wang","name":"Wang Y"},{"initials":"W","lastname":"Rountree","name":"Rountree W"},{"initials":"KO","lastname":"Saunders","name":"Saunders KO"},{"initials":"G","lastname":"Ferrari","name":"Ferrari G"},{"initials":"P","lastname":"Borrow","name":"Borrow P"},{"initials":"EY","lastname":"Jones","name":"Jones EY"},{"initials":"SM","lastname":"Alam","name":"Alam SM"},{"initials":"ML","lastname":"Azoitei","name":"Azoitei ML"},{"initials":"GM","lastname":"Gillespie","name":"Gillespie GM"},{"initials":"AJ","lastname":"McMichael","name":"McMichael AJ"},{"initials":"BF","lastname":"Haynes","name":"Haynes BF"}],"identifier":[{"id":"10.1038/s42003-022-03183-5","type":"doi"},{"id":"35347236","type":"pubmed"}],"issue":["1"],"journal":{"iso_abbreviation":"Commun Biol","name":""},"pages":["271"],"title":"Mouse and human antibodies bind HLA-E-leader peptide complexes and enhance NK cell cytotoxicity.","type":"article","url":"https://www.nature.com/articles/s42003-022-03183-5","volume":["5"],"year":[2022]},"in_pmc":"N","in_pmce":"Y","open_access":"Y"},"resolution":"1.80","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/7bh8"},"rcsb":{"url":"https://www.rcsb.org/structure/7bh8"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":null,"title":"HLA-E*01:03 binding \"VMAPRTVLL\" with antibody at 1.80&#8491; resolution","unique_chain_count":5}}