The Self-Specific Activation Receptor SLAM Family Is Critical for NK Cell Education

NK cell education, a term describing a process for NK cell acquisition of functional competence, is primarily achieved by self-MHC-I-specific inhibitory receptors. In this study, we have demonstrated that SLAM family receptors (SFRs) redundantly expressed on hematopoietic cells function as self-specific activation receptors critical for NK cell education. To overcome gene redundancy, we generated mice simultaneously lacking seven SFRs, revealing that NK-cell-mediated rejection of semi-allogeneic hematopoietic cells largely depended on the presence of SFRs on target cells. This stimulatory effect was determined by the presence of SFR-coupled adaptors; however, SFR-deficient mice displayed enhanced reactivity to hematopoietic cells. These findings demonstrate that SFRs endow NK cells with an ability to kill hematopoietic cells during the effector phase; however, the sustained engagement of SFRs can desensitize NK cell responses during an education process. Therefore, self-specific activating ligands may be “tolerogens” for NK cells, akin to self-antigens that induce T cell tolerance. [Display omitted] •Mice lacking seven SFR members were generated using the sequential CRISPR technique•SFR-deficient NK cells displayed enhanced reactivity against hematopoietic cells•SFRs acted as activation receptors in NK cell rejection of hematopoietic cells•Chronic engagement of activating SFRs desensitized NK cell responsiveness NK cell education describes a process for NK cell acquisition of functional competence, which is primarily achieved by self-MHC-I-specific inhibitory receptors. Dong and colleagues demonstrate that the self-specific activation receptor SLAM family is critical for NK cell education and activation.