Mouse and human antibodies bind HLA-E-leader peptide complexes and enhance NK cell cytotoxicity

• Main Authors: Alam, S.M (Author), Azoitei, M.L (Author), Barr, M. (Author), Borrow, P. (Author), Brackenridge, S. (Author), Cain, D.W (Author), Edwards, R.J (Author), Ferrari, G. (Author), Gillespie, G.M (Author), Harlos, K. (Author), Haynes, B.F (Author), Jones, E.Y (Author), Li, D. (Author), McMichael, A.J (Author), Mu, Z. (Author), Parks, R. (Author), Quastel, M. (Author), Rountree, W. (Author), Rozbesky, D. (Author), Saunders, K.O (Author), Scearce, R.M (Author), Swanson, O. (Author), Walters, L.C (Author), Wang, Y. (Author), Wiehe, K. (Author)
• Format: Article
• Language: English
• Published: Nature Research 2022
• Subjects: animal; Animals; cytotoxicity; Cytotoxicity, Immunologic; genetics; Histocompatibility Antigens Class I; HLA antigen; HLA antigen class 1; HLA Antigens; HLA-E antigen; human; Humans; immunoglobulin; Immunoglobulins; Killer Cells, Natural; metabolism; Mice; mouse; natural killer cell; peptide; Peptides; Protein Sorting Signals; signal peptide
• Online Access: View Fulltext in Publisher
• ISBN: 23993642 (ISSN)
• DOI: 10.1038/s42003-022-03183-5

The 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+ 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 naïve B cells of cytomegalovirus (CMV)-negative, healthy humans. Thus, HLA-E-VL9-targeting mouse and human antibodies isolated from the naïve B cell antibody pool have the capacity to enhance NK cell cytotoxicity. © 2022, The Author(s).