HLA-F Gene - Structure, Function, and Clinical Significance

HLA-F is a non-classical major histocompatibility complex (MHC) class I gene located on chromosome 6p21.33 within the MHC region. Unlike classical MHC class I molecules (HLA-A, -B, -C), HLA-F has limited polymorphism and is expressed on the cell surface primarily as an open conformer (without peptide) or in complex with other molecules. It functions as a ligand for inhibitory and activating receptors on natural killer (NK) cells and other immune cells, modulating immune responses. HLA-F is expressed in various tissues, including lymphoid organs, placenta, and certain cancers, and has been implicated in pregnancy, viral infection, and tumor immune evasion.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Immune System (Reactome: R-HSA-168256)

• Adaptive Immune System (Reactome: R-HSA-1280218)

• Class I MHC mediated antigen processing & presentation (Reactome: R-HSA-983169)

• NK cell mediated cytotoxicity (KEGG: hsa04650)

• Antigen processing and presentation (KEGG: hsa04612)

HLA-F is a 40.5 kDa glycoprotein composed of an alpha chain (heavy chain) non-covalently associated with beta-2-microglobulin. It has a typical MHC class I structure with three extracellular domains (α1, α2, α3), a transmembrane region, and a short cytoplasmic tail. Unlike classical MHC molecules, HLA-F predominantly exists as an open conformer lacking a bound peptide, allowing it to interact with a distinct set of receptors, including KIR3DS1 and LILRB1/2. Its expression is upregulated by interferons and during cellular stress. HLA-F plays a role in immune modulation, particularly in NK cell regulation, and its aberrant expression is linked to pregnancy complications, viral infections, and cancer.