Cis association of leukocyte Ig‐like receptor 1 with MHC class I modulates accessibility to antibodies and HCMV UL18

Leukocyte Ig‐like receptor (LIR) 1 (CD85j/ILT2/LILRB1) is an inhibitory receptor with broad specificity for MHC class I (MHC‐I) and the human CMV MHC‐I homologue UL18. LIR‐1 can inhibit NK cells through the conventional interaction with MHC‐I expressed on a target cell (in trans) but the nature and the effects of LIR‐1 interactions with MHC‐I in cis are not well understood. Here we show that MHC‐I expressed in cis has an impact on the detection of LIR‐1 with various antibodies. We found the cis interaction alters recognition by only one of two antibodies known to block functional trans recognition by LIR‐1 on NK cells. Specifically, we observed an enhancement of recognition with GHI/75 in the presence of various MHC‐I alleles on 721.221 cells. We found that blocking the LIR‐1 contact site with anti‐MHC‐I antibodies decreased detection of LIR‐1 with GHI/75. We also observed a decrease in GHI/75 following acid denaturation of MHC‐I. Finally, disruption of LIR‐1 cis interactions with MHC‐I significantly enhanced UL18‐Fc binding to NK92 cells and enhanced the relative inhibition of NK92 cells by HLA‐G. These results have implications for LIR‐1 function in scenarios such as infection when MHC‐I levels on effector cells may be increased by IFNs.