| HLA‑G is a nonclassical MHC class I molecule of the HLA‑Ib family with restricted expression and a key role in dampening immune responses at sites where tolerance is needed. HLA‑G transcripts undergo alternative splicing to generate several membrane‑bound and soluble isoforms that share the basic MHC class I organization, with α1, α2, and α3 domains associated with β2‑microglobulin, while some shorter or soluble forms differ in domain content and how they are displayed or released. Many isoforms can form disulfide‑linked dimers through a conserved cysteine residue, and this multimeric state increases the apparent affinity of HLA‑G for inhibitory receptors on immune cells. HLA‑G directly binds ILT2 on T, B, and NK cells, ILT4 on monocytes and dendritic cells, and KIR2DL4 on specific NK and T‑cell subsets, and these interactions trigger ITIM‑based signaling that recruits phosphatases, lowers activation thresholds, and reduces cytotoxic granule exocytosis and inflammatory cytokine production. These receptor pathways also support regulatory T‑cell expansion and favor tolerogenic differentiation of antigen‑presenting cells, so HLA‑G expression shifts local immune balance away from strong effector responses and toward controlled, non‑damaging activity. At the maternal–fetal interface, trophoblast HLA‑G restrains uterine NK and effector T cells and conditions decidual myeloid cells, which allows fetal tissues carrying paternal antigens to develop in an environment of active but moderated immunity. Expression levels and isoform patterns are shaped by polymorphisms in the HLA‑G promoter and 3′UTR, which influence transcription, mRNA stability, and microRNA binding, leading to individual variation in the strength of HLA‑G–mediated inhibition and in susceptibility to tolerance‑related or inflammatory conditions. Many tumors and chronically inflamed tissues show increased HLA‑G at the surface or as soluble protein in the microenvironment, where sustained engagement of ILT2, ILT4, and KIR2DL4 on infiltrating lymphoid and myeloid cells weakens anti‑tumor cytotoxicity and favors accumulation of suppressive populations. |
