Combinatorial Expression of NK Cell Receptors Governs Cell Subset Reactivity and Effector Functions But Not Tumor Specificity

Natural Killer (NK) cell receptors allow NK cells to recognize targets such as tumor cells. Many of them are expressed on a subset of NK cells, independently of each other, which creates a vast diversity of receptor combinations. Whether these combinations influence NK cell anti-tumor responses is not well understood. We addressed this question in the C57BL/6 mouse model and analyzed the individual effector response of 444 mouse NK cell subsets, defined by combinations of 12 receptors, against tumor cell lines of different tissue origins. We found a wide range of reactivity among NK subsets, but the same hierarchy of responses was observed for the different tumor types, showing that the repertoire of NK cell receptors does not encode for different tumor specificities but for different intrinsic reactivities. The co-expression of CD27, NKG2A, and DNAM-1 identified subsets with relative cytotoxic specialization, while reciprocally CD11b and KLRG1 defined best IFNg producers. The expression of educating receptors Ly49C, Ly49I, and NKG2A was also strongly correlated with IFNg production but this effect was suppressed by unengaged receptors Ly49A, Ly49F, and Ly49G2. Finally, IL-15 coordinated NK cell effector functions but education and unbound inhibitory receptors retained some influence on their response. Collectively, these data refine our understanding of the mechanisms governing NK cell reactivity, which could help design new NK cell therapy protocols.