KIR2DS1 positive Natural Killer cells from individuals expressing cognate HLA ligand are tolerant.

Inhibitory KIR-HLA interactions are critical for NK tolerance to self. KIR2DS1 is the only activating counterpart of inhibitory KIRs to have ligand specificity for HLA class I, recognizing HLA-C group 2. Since KIR and HLA genes segregate independently, individuals that carry KIR2DS1 may have HLA-C antigens of the HLA-KIR ligand group C2. We here report that 2DS1 positive NK cells from such individuals are tolerant to such self HLA antigens. We demonstrate that the mechanism for tolerance is different for individuals homozygous or heterozygous for the HLA ligand. NK clones have been generated from KIR2DS1-positive and HLA-C2 homozygous, HLA-C1/C2 heterozygous or HLA-C1 homozygous individuals. Their response against HLA-KIR ligand group C2-expressing targets and their KIR repertoire have been assessed. NK clones expressing KIR2DS1 display anti-HLA-C2 alloreactivity but are tolerant to HLA-C2 if this is a self antigen. This hyporesponsiveness to C2 in C2/C2 homozygous donors is also observed for NK clones lacking 2DL1. In turn, the co-expression of inhibitory KIRs with ligand specificity for self HLA class I including C2 is an important mechanism for tolerance in HLA-C1/C2 heterozygous individuals. This is the first demonstration of activating NK receptor tolerance to cognate self MHC ligand. NK clones expressing only the activating receptor and not the homologous inhibitory receptor are readily identified. Remarkably, NK clones with self HLA ligand specificity are not deleted.