Major histocompatibility complex class I antigen G (HLA-G)

Major histocompatibility complex class I antigen G (HLA-G) is a nonclassical MHC class I molecule distinguished by its restricted tissue distribution, primarily at the fetal–maternal interface, and its unique peptide-binding characteristics[2][3]. HLA-G exists in seven isoforms generated by alternative splicing, including both membrane-bound and soluble forms[1][2]. Structurally, HLA-G comprises a heavy chain with α1, α2, and α3 domains, non-covalently associated with β2-microglobulin; the α1 and α2 domains form a peptide-binding cleft, allowing the presentation of a limited repertoire of antigenic peptides[1][2][3][4]. Functionally, HLA-G plays a key role in immune tolerance, notably protecting the fetus from maternal immune attack and serving as an immune checkpoint molecule in cancer and transplantation contexts[1][2][3]. It interacts with inhibitory immune receptors such as LIR-1 and LIR-2, leading to the suppression of NK cells, T cells, and antigen-presenting cell responses[3][4]. Elevated HLA-G expression can be associated with poor tumor immune surveillance and may predict graft acceptance in transplantation[2]. Therapeutic targeting of HLA-G is a developing area, with experimental agents aiming to restore antitumor immunity or enhance transplantation outcomes[1][2].

Other names

HLA class I histocompatibility antigen, alpha chain GSoluble HLA class I histocompatibility antigen, alpha chain GHLAGHLA-6.0sHLA-GHLA G antigenMHC class I antigen GMHC-GHLA-G histocompatibility antigenMHC class Ib antigenMutant MHC class I antigenMutant MHC class Ib antigen

For experimental drugs: Blockade or enhancement of HLA-G-mediated inhibition of immune cell activation Modulation of immune checkpoint pathways (e.g., by targeting HLA-G–LIR1/2 interactions)[1][3][4]