Discovery of LILRA7 as a novel immune receptor reintroduced into humans by archaic introgression

The leukocyte receptor complex (LRC) is one of the most polymorphic regions in the human genome and encodes multigene families of innate immune receptors, including leukocyte immunoglobulin-like receptors (LILRs). However, high sequence similarity among LRC genes has hindered comprehensive characterization of this region. Here we identify a previously unrecognized 11.3‑kb insertion located between the LILRB2 and LILRA3 genes that exhibits a LILR exon–intron organization. This discovered gene was formally approved and assigned the name LILRA7 by the HUGO Gene Nomenclature Committee following this study. LILRA7 encodes an activating immune receptor comprising four Ig‑like domains. A monoclonal antibody specific for LILRA7 confirmed surface expression on monocytes and neutrophils, suggesting its involvement in innate immune responses. LILRA7 has been detected in South Asian, East Asian, and European populations but is absent in African populations. Furthermore, LILRA7 orthologs are conserved in great apes. Notably, the LILRA7 gene is also present in Neanderthal and Denisovan genomes. These findings support a model in which LILRA7 was lost in the lineage leading to modern humans and subsequently reintroduced into non‑African populations through archaic hominin introgression. Collectively, our results uncover an ancient human immune receptor with implications for population‑specific immunity and human evolutionary history.