How do NK cells sense the expression of HLA-G class Ib molecules?

The nature of NK cell receptors involved in recognition of HLA-G1 has remained an unclear issue; we herein review this topic based on our experience. We found no evidence that well characterized p58 and p70 KIRs may interact with HLA-G1. By contrast, our data support that NK recognition of cells expressing HLA-G1 involves at least two non-overlapping receptor-ligand systems: (1) the direct engagement of the ILT2 (LIR1) receptor by HLA-G1; and (2) the interaction of CD94/NKG2A and CD94/NKG2C receptors with the non-classical class I molecule HLA-E, co-expressed on the surface upon binding to a nonamer (VMAPRTLFL) from the HLA-G leader sequence.