Cytotoxic activity of natural killer cells lacking killer-inhibitory receptors for self-HLA class I molecules against autologous hematopoietic stem cells in healthy individuals

Abstract

Killer-inhibitory receptors (KIR) are receptors for self-HLA class I molecules, which are expressed on natural killer (NK) cells and small subsets of T-lymphocytes. KIR receptors that do not bind to self-HLA class I have been implicated in the pathogenesis of pure red-cell aplasia and other autoimmune diseases. However, NK cells whose inhibitory receptors lack any apparent self-ligand can also be found in healthy individuals. We therefore tested whether these NK cells are capable of exerting cytotoxic activity against autologous CD34(+) hematopoietic precursors. We detected NK cells whose sole inhibitory receptors were CD94/NKG2-A and that had no affinity for autologous HLA-C molecules. In vitro, such cells were able to kill autologous CD34(+) stem cells that expressed MHC class I antigen at a high level in about 50% of the cases of HLA-C group 2 donors. Two individual clones derived from this NK subpopulation were stimulated by autologous HLA-Cw5/6-positive stem cells, but not by allogeneic HLA-Cw7-positive stem cells. Our findings demonstrate the presence of potentially autoreactive natural killer cells in otherwise healthy individuals.