A "chimeric" C57L-derived Ly49 inhibitory receptor resembling the Ly49D activation receptor

Ly49D is a natural killer (NK) cell activation receptor that is responsible for differential mouse inbred strain-determined lysis of Chinese hamster o vary (CHO) cells. Whereas C57BL/6 NK cells kill CHO, BALB/c-derived NK cell s cannot kill because they lack expression of Ly49D. Furthermore, the expre ssion of Ly49D, as detected by monoclonal antibody 4E4, correlates well wit h CHO lysis by NK cells from different inbred strains. However, one discord ant mouse strain was identified; C57L NK cells express the mAb 4E4 epitope but fail to lyse CHO cells, Herein we describe a Ly49 molecule isolated fro m C57L mice that is recognized by mAb 4E4 (anti-Ly49D). Interestingly, this molecule shares extensive similarity to Ly49D(B6) in its extracellular dom ain, but its cytoplasmic and transmembrane domains are identical to the inh ibitory receptor Ly49A(B6), including a cytoplasmic ITIM, This molecule bea rs substantial overall homology to the previously cloned Ly490 molecule fro m 129 mice the serologic reactivity and function of which were undefined. C ytotoxicity experiments revealed that 4E4(+) LAK cells from C57L mice faile d to lyse CHO cells and inhibited NK cell function in redirected inhibition assays. MHC class I tetramer staining revealed that the Ly490(C57L) bound H-2D(d) and lysis by 4E4+ C57L LAK cells is inhibited by target H-2Dd. The structural basis for ligand binding was also examined in the context of the recent crystallization of a Ly49A-H-2D(d) complex. Therefore, this apparen tly "chimeric"' Ly49 molecule serologically resembles an NK cell activation receptor but functions as an inhibitory receptor, (C) 2001 Academic Press.