HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A

TLDR

HLA‑E surface expression on cells requires a nonamer peptide from HLA class I signal sequences and is ubiquitously present on many cell types. The study aimed to determine whether HLA‑E can shield HLA class I transfectants from natural killer cell–mediated lysis. Using 721.221 cells transfected with various HLA class I allotypes, the authors showed that peptide‑loaded HLA‑E protects cells from NK lysis through CD94/NKG2A recognition, as blocking antibodies to HLA‑E, CD94, or CD94/NKG2A restored lysis. HLA‑E specifically engages the CD94/NKG2A inhibitory receptor to prevent NK cell killing, while it does not inhibit via other Ig‑SF or ILT2/LIR1 receptors.

Abstract

We previously showed that the availability of a nonamer peptide derived from certain HLA class I signal sequences is a necessary requirement for the stabilization of endogenous HLA-E expression on the surface of 721.221 cells. This led us to examine the ability of HLA-E to protect HLA class I transfectants from natural killer (NK) cell-mediated lysis. It was possible to implicate the CD94/NKG2A complex as an inhibitory receptor recognizing this class Ib molecule by using as target a .221 transfectant selectively expressing surface HLA-E. HLA-E had no apparent inhibitory effect mediated through the identified Ig superfamily (Ig-SF) human killer cell inhibitory receptors or ILT2/LIR1. Further studies of CD94/NKG2+ NK cell-mediated recognition of .221 cells transfected with different HLA class I allotypes (i.e., -Cw4, -Cw3, -B7) confirmed that the inhibitory interaction was mediated by CD94/NKG2A recognizing the surface HLA-E molecule, because only antibodies directed against either HLA-E, CD94, or CD94/NKG2A specifically restored lysis. Surface stabilization of HLA-E in cold-treated .221 cells loaded with appropriate peptides was sufficient to confer protection, resulting from recognition of the HLA class Ib molecule by the CD94/NKG2A inhibitory receptor. Consistent with the prediction that the ligand for CD94/NKG2A is expressed ubiquitously, our examination of HLA-E antigen distribution indicated that it is detectable on the surface of a wide variety of cell types.