Cutting edge: Expression of functional CD94/NKG2A inhibitory receptors on fetal NK1.1⁺Ly-49^- cells: A possible mechanism of tolerance during NK cell development

Fetal liver- and thymus-derived NK1.1⁺ cells do not express known Ly- 49 receptors. Despite the absence of Ly-49 inhibitory receptors, fetal and neonatal NK1.1⁺Ly-49^- cells can distinguish between class I(high) and class I(low) target cells, suggesting the existence of other class I-specific inhibitory receptors. We demonstrate that fetal NK1.1⁺Ly-49^- cell lysates contain CD94 protein and that a significant proportion of fetal NK cells are bound by Qa1^b tetramers. Fetal and adult NK cells efficiently lyse lymphoblasts from K(b-/-)D(b-/-) mice. Qa1^b-specific peptides Qdm and HLA- CW4 leader peptide specifically inhibited the lysis of these blasts by adult and fetal NK cells. Qdm peptide also inhibited the lysis of Qa1^b-transfected human 721.221 cells by fetal NK cells. Taken together, these results suggest that the CD94/NKG2A receptor complex is the major known inhibitory receptor for class I (Qa1^b) molecules on developing fetal NK cells.