The AP-1 transcription factor JunD activates the leukocyte immunoglobulin-like receptor 1 distal promoter

Leukocyte immunoglobulin-like receptor 1 (LILRB1) is an inhibitory receptor that binds classical and non-classical MHC-I as well as UL18, a viral MHC-I homolog. LILRB1 is encoded within the leukocyte receptor complex and is widely expressed on immune cells. Two distinct promoters used differentially by lymphoid and myeloid cells were previously identified, but little is known regarding molecular regulation of each promoter or cell-type-specific usage. Here, we have investigated the transcriptional regulation of human LILRB1 focusing on elements that drive expression in NK cells. We found that while both the distal and proximal promoter regions are active in reporter plasmids in lymphoid and myeloid cells, the proximal promoter is used minimally to transcribe LILRB1 in NK cells compared with monocytes. We defined a 120-bp core region of transcriptional activity in the distal promoter that can bind several factors in NK cell nuclear extracts. Within this region, we investigated overlapping putative AP-1 sites. An inhibitor of JNK decreased LILRB1 transcript in a LILRB1⁺ NK cell line. Upon examining binding of specific AP-1 factors, we found JunD associated with the LILRB1 distal promoter. Finally, depletion of JunD led to a decrease in distal promoter transcript, indicating an activating role for JunD in regulation of LILRB1 transcription. This study presents the first description of regions/factors required for activity of the LILRB1 distal promoter, the first description of a role for JunD in NK cells and suggests a potential mechanism for dynamic regulation of LILRB1 by cytokines.