IgM Natural Antibodies Bind HLA-E-Leader Peptide Complexes and Modulate NK Cell Cytotoxicity

Li, D.; Brackenridge, S.; Walters, L. C.; Harlos, K.; Rozbesky, D.; Cain, D. W.; Wiehe, K.; Scearce, R. M.; Barr, M.; Mu, Z.; Parks, R.; Quastel, M.; Edwards, R. J.; Alam, S. M.; Saunders, K. O.; Borrow, P.; Jones, E. Y.; Gillespie, G. M.; McMichael, A. J.; Haynes, B. F.

doi:10.1101/2020.12.03.403014

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bioRxiv · 10.1101/2020.12.03.403014

IgM Natural Antibodies Bind HLA-E-Leader Peptide Complexes and Modulate NK Cell Cytotoxicity

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Abstract

HLA-E is a non-classical class Ib molecule that has limited polymorphism and binds 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 isolated a murine IgM antibody 3H4, that specifically recognized HLA-E-VL9 bound complexes and enhanced killing of HLA-E-VL9-expressing cells by an NKG2A+ NK cell line. Structural analysis revealed how 3H4 prevents CD94/NKG2A docking on HLA-E-VL9 by binding with an overlapping footprint. Upon in vitro maturation, an affinity-optimized 3H4 IgG showed enhanced NK killing of HLA-E-VL9-expressing cells. Remarkably, HLA-E-VL9-specific IgM autoantibodies with similar specificity and functions to 3H4 were subsequently isolated from naive B cells of cytomegalovirus (CMV)-negative, healthy male human donors. Thus, a repertoire of germline low affinity HLA-E-VL9-reactive antibodies are present in both naive human and murine B cell repertoires. These antibodies can enhance NK cell cytotoxicity and therefore have potential for therapeutic modulation of NK cell function.

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Li, D., Brackenridge, S., Walters, L. C., Harlos, K., Rozbesky, D., Cain, D. W., Wiehe, K., Scearce, R. M., Barr, M., Mu, Z., Parks, R., Quastel, M., Edwards, R. J., Alam, S. M., Saunders, K. O., Borrow, P., Jones, E. Y., Gillespie, G. M., McMichael, A. J., Haynes, B. F.. 2020-12-03. IgM Natural Antibodies Bind HLA-E-Leader Peptide Complexes and Modulate NK Cell Cytotoxicity. https://doi.org/10.1101/2020.12.03.403014

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