Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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 naïve 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 naïve human and murine B cell repertoires. These antibodies can enhance NK cell cytotoxicity and therefore have potential for therapeutic modulation of NK cell function.

Original publication

DOI

10.1101/2020.12.03.403014

Type

Journal article

Publication Date

2020