Human leukocyte antigen F (HLA-F)

Human leukocyte antigen F (HLA-F) is a non-classical MHC class I molecule of the immune system, structurally related to classical HLA-I molecules but with distinct features and functions. Unlike typical classical MHC-I proteins, which present endogenous peptides to cytotoxic T cells, HLA-F primarily functions as an immune regulator, particularly through interactions with natural killer (NK) cell receptors (including KIR3DS1, KIR3DL2, LILRB1/ILT2, and ILT4) and, potentially, with T cells. HLA-F has the unique ability to exist in two key forms: a "peptide-bound" form (complexed with β2-microglobulin and often presenting long, unconventional peptides—sometimes with post-translational modifications, such as phosphorylation) and an "open conformer" form (without peptide or β2-microglobulin). HLA-F surface expression and conformation signal important immune states, such as pregnancy (maternal-fetal interface), inflammation, infection (including HIV), and possibly tumor or neuronal immune surveillance. Its regulatory activities are critical for modulating NK cell and CD8+ T cell responses and establishing immune tolerance—including prevention of maternal immune attack on the fetus—primarily by engaging inhibitory or activating NK cell receptors. Its abnormal expression or function may contribute to autoimmune disease, infection susceptibility, or cancer immune escape mechanisms[1][2][3].

Other names

HLA class I histocompatibility antigen, alpha chain FHLAFHLA-F antigenLeukocyte antigen FMHC class I antigen FCDA12HLA-5.4HLA-CDA12HLA-F {ECO:0000303|PubMed:1688605, ECO:0000303|PubMed:1707659, ECO:0000312|HGNC:HGNC:4963}non-classical MHC class I antigen

- Acts as ligand for LILRB1/ILT2 (inhibitory receptor), modulating immune cell response[3][1][2] - Serves as ligand for KIR3DS1 (activating) and KIR3DL2 (inhibitory) killer immunoglobulin-like receptors on NK cells, modulating their cytotoxic activity[1][3][2] - May present non-canonical (often post-translationally modified) self-peptides, influencing T cell and NK cell recognition[1][3] - Modulates cross-presentation with other open conformer MHCs, participating in exogenous antigen presentation to CD8+ T cells[3][1]