| HLA‑E is a nonclassical MHC class I molecule of the HLA‑Ib family with very limited polymorphism that forms a heterodimer of a heavy chain with α1, α2, and α3 domains and β2‑microglobulin and presents a restricted peptide repertoire dominated by a conserved VL9 nonamer derived from the signal sequences of HLA‑A, ‑B, ‑C, and ‑G. The peptide‑binding groove shares the framework of classical HLA‑I molecules but contains adaptations along all binding pockets that impose high specificity for VL9‑type peptides, using side‑chain contacts across the length of the groove to favor these signal‑peptide–derived ligands and to support relatively stable peptide‑receptive HLA‑E–β2m complexes that can also accommodate weaker pathogen‑derived peptides. HLA‑E–peptide complexes are transported to the cell surface and interact with CD94/NKG2x receptors on NK cells and subsets of CD8⁺ T cells; engagement of inhibitory CD94/NKG2A or NKG2B through ITIM motifs reduces NK cytotoxicity and IFN‑γ production, whereas engagement of activating CD94/NKG2C via the DAP12 ITAM adaptor promotes NK cell activation, expansion of adaptive‑like NK subsets, and enhanced effector function during viral infection. CD94/NKG2 receptors dock across the α1/α2 platform and bind peptide, with the VL9 sequence contributing directly to the receptor interface, so changes in signal peptide supply or sequence modulate receptor affinity and the balance between inhibitory and activating signaling. HLA‑E also presents diverse non‑VL9 peptides from bacteria and viruses to CD8⁺ T cells, and HLA‑E–restricted TCRs recognize these complexes and trigger classical CD3‑ζ ITAM, ZAP‑70, LAT, PI3K, MAPK, NF‑κB, and NFAT signaling cascades that support cytotoxic activity and cytokine production, adding an adaptive arm to HLA‑E biology. Regulation of HLA‑E expression and trafficking depends on TAP‑mediated peptide loading and intracellular transport routes distinct from some classical HLA‑I molecules, and soluble HLA‑E shed from endothelial cells and other tissues has been described as an additional immunoregulatory form capable of engaging CD94/NKG2 receptors. Many viruses and tumors modulate HLA‑E by altering leader peptide availability, inducing expression, or contributing their own peptides that bind HLA‑E and preferentially signal through inhibitory NKG2A, and high HLA‑E in several malignancies associates with impaired NK and T‑cell responses and immune escape. |
