Abstract Natural Killer (NK) cells are a major subset of innate immune cells that are essential for host defense against pathogens and cancer. Two main classes of inhibitory NK receptors (NKR), KIR and CD94/NKG2A, play a key role in suppressing NK activity upon engagement with tumor cells or virus infected cells, limiting their antitumor and antiviral activity. Here, we find that single-chain mouse NKR antagonists linked to a VHH that binds the cell surface phosphatase CD45 potentiate NK and T activity to a greater extent than NKR blocking antibodies alone in vitro . We also uncovered crosstalk between mouse NKG2A and Ly49 that collectively inhibit NK cell activation, such that CD45-NKG2A and CD45-Ly49 bispecific molecules show synergistic effects in their ability to enhance NK cell activation. The basis of the activity enhancement by CD45 ligation may reflect greater antagonism of inhibitory signaling from engagement of MHC I on target cells, combined with other mechanisms, including avidity effects, tonic signaling, antagonism of weak inhibition from engagement of MHC I on non-target cells and possibly CD45 segregation within the NK cell-target cell synapse. These engineered ligands uncover a mechanism for enhancing the activity of mouse NK and T cells that merits evaluation in the context of human NKR antagonist cancer immunotherapies.
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