Protein Expression and Peptide Binding Suggest Unique and Interacting Functional Roles for HLA-E, F, and G in Maternal-Placental Immune Recognition

TLDR

The study investigates the structure and expression of HLA‑E, F, and G class I complexes in placental tissue. The authors performed structural analysis of peptides bound to soluble and membrane HLA‑G from placenta and used novel antibodies to assess expression of HLA‑E, F, and G in placental tissues. Placental HLA‑G binds fewer distinct peptides than transfectant‑derived HLA‑G, with a single cytokine‑derived peptide comprising 15 % of the bound pool; HLA‑G is expressed membrane‑bound in extravillous trophoblasts and soluble in all trophoblasts, HLA‑E co‑expresses with HLA‑G signal‑sequence peptides, and HLA‑F is surface‑localized on invading extravillous trophoblasts, marking the first cells to express all three nonclassical HLA class I antigens simultaneously.

Abstract

Abstract In this study we focused on the structure and expression of the HLA-E, F, and G class I complexes in placental tissue. Structural analysis included an examination of the peptides bound to soluble and membrane forms of the HLA-G complex isolated directly from placenta. An important distinction was observed from HLA-G bound peptides previously isolated from transfectant cells. Thus, the number of distinct moieties bound to placental-derived proteins was substantially lower than that bound to transfectant-derived HLA-G. Indeed, a single peptide species derived from a cytokine-related protein alone accounted for 15% of the molar ratio of HLA-G bound peptide. To further examine HLA-E and its potential to bind peptide, notably that derived from HLA-G, we combined new Abs to examine expression in placental tissues for all the known forms of the nonclassical class I molecules. Whereas membrane HLA-G was found in extravillous trophoblasts, soluble HLA-G was found in all placental trophoblasts, including villous cytotrophoblasts and syncitiotrophoblasts. Further, HLA-E was found in all cells that expressed either form of HLA-G, consistent with HLA-E being complexed with the HLA-G signal sequence-derived nonamer in these cells. Finally, using new reagents specific for HLA-F, a restricted pattern of expression was observed, primarily on extravillous trophoblasts that had invaded the maternal decidua. Comparative staining indicated that HLA-F was on the surface of these cells, defining them as the first to demonstrate surface expression of this Ag and the first cell type identified to express all three nonclassical HLA class I Ags simultaneously.