IgM Natural Antibodies Bind HLA-E-Leader Peptide Complexes and Modulate NK Cell Cytotoxicity
Li D., Brackenridge S., Walters LC., Harlos K., Rozbesky D., Cain DW., Wiehe K., Scearce RM., Barr M., Mu Z., Parks R., Quastel M., Edwards RJ., Alam SM., Saunders KO., Borrow P., Jones EY., Gillespie GM., McMichael AJ., Haynes BF.
ABSTRACTThe non-classical class Ib molecule human leukocyte antigen E (HLA-E) has limited polymorphism and can bind HLA class Ia leader sequence peptides (VL9). HLA-E-VL9 complexes interact with the natural killer (NK) cell inhibitory receptor NKG2A/CD94 and regulate NK cell-mediated cytotoxicity. Here we report a murine HLA-E-VL9-specific IgM monoclonal antibody 3H4 that enhanced killing of HLA-E-VL9-expressing target cells by a NKG2A+ NK cell line, most likely due to steric clashes between 3H4 and CD94/NKG2A when docked on the HLA-E-VL9 surface as determined by a 1.8 Å co-complex crystal structure. Key 3H4-mediated contacts with HLA-E-VL9 were generated by germline-encoded CDR-H3 residues. Human IgM HLA-E-VL9 reactive antibodies could also be isolated from CD10−/CD27- naïve B cells; these antibodies also recognized microbiome-derived peptides presented by HLA-E. Thus, a subset of natural antibodies that recognize VL9-bound HLA-E exist as part of the normal Ig repertoire with capacity to regulate NK cell function.