HLA-H*02:07 Is a Membrane-Bound Ligand of Denisovan Origin That Protects against Lysis by Activated Immune Effectors

Abstract

The biological relevance of genes initially categorized as "pseudogenes" is slowly emerging, notably in innate immunity. In the HLA region on chromosome 6, <i>HLA-H</i> is one such pseudogene; yet, it is transcribed, and its variation is associated with immune properties. Furthermore, two <i>HLA-H</i> alleles, <i>H</i>*<i>02:07</i> and <i>H</i>*<i>02:14</i>, putatively encode a complete, membrane-bound HLA protein. Here we thus hypothesized that HLA-H contributes to immune homeostasis similarly to tolerogenic molecules HLA-G, -E, and -F. We tested if <i>HLA-H</i>*<i>02:07</i> encodes a membrane-bound protein that can inhibit the cytotoxicity of effector cells. We used an HLA-null human erythroblast cell line transduced with <i>HLA-H</i>*<i>02:07</i> cDNA to demonstrate that HLA-H*02:07 encodes a membrane-bound protein. Additionally, using a cytotoxicity assay, our results support that K562 <i>HLA-H</i>*<i>02:07</i> inhibits human effector IL-2-activated PBMCs and human IL-2-independent NK92-MI cell line activity. Finally, through in silico genotyping of the Denisovan genome and haplotypic association with Denisovan-derived <i>HLA-A</i>*<i>11</i>, we also show that <i>H</i>*<i>02:07</i> is of archaic origin. Hence, admixture with archaic humans brought a functional <i>HLA-H</i> allele into modern European and Asian populations.