NK cell licensing and missing self-recognition can be mediated by a single member of the Ly49 family 4220

Abstract Description Natural killer (NK) cells recognize target cells through germline-encoded activation and inhibitory receptors enabling effective immunity against viruses and cancer. The Ly49 receptor family in the mouse and killer immunoglobin-like receptor (KIR) family in humans play a central role in NK cell immunity through recognition of MHC class I and related molecules. These receptor families are involved in licensing and rejection of MHC-I-deficient cells through missing-self. It has been challenging to attribute individual Ly49 receptors to NK cell function, because the Ly49 family is highly polymorphic and some Ly49s have overlapping functions, Herein, we generated a novel mouse strain that lacks expression of all Ly49s. These mice were unable to reject missing-self target cells in vivo, were defective in NK cell licensing, and displayed lower KLRG1 on the surface of NK cells. To study the role of an individual Ly49 receptor, we crossed the Ly49-deficient mice to Ly49A knock-in mice that also expressed its cognate ligand H-2Dd. These mice showed restored missing-self target cell rejection, NK cell licensing, and NK cell KLRG1 expression. Thus, a single inhibitory receptor of the Ly49 family is sufficient to license NK cells and mediate missing-self in vivo. Funding Sources This work was supported by National Institutes of Health grants R01-AI129545. Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)