HLA-F gene

The HLA-F gene (HLA-F stands for: Major Histocompatibility Complex, Class I, F) is a protein-coding gene located on chromosome 6p22.1. The HLA-F gene has only a few polymorphisms. Several transcript variants coding for different isoforms have been found for this gene. These variants lack a coding exon that is found in transcripts of other HLA paralogs due to an altered splice acceptor site, resulting in a shorter cytoplasmic domain. An important paralog of this gene is HLA-B.

The protein encoded by this gene is a non-classical major histocompatibility class Ib molecule thought to play a role in immune surveillance, immune tolerance and inflammation. Functions in two forms, as a heterotrimeric complex with B2M/beta-2 microglobulin and a peptide (peptide-bound HLA-F-B2M) and as an open conformation (OC) without peptide and B2M (peptide-free OC). In complex with B2M, it presents non-canonical self-peptides that carry post-translational modifications, in particular phosphorylated self-peptides.

Peptide-bound HLA-F-B2M acts as a ligand for the inhibitory receptor LILRB1, which plays an important role in maternal-fetal tolerance.

Peptide-free OC acts as a ligand for the receptors KIR3DS1 and KIR3DL2. When interacting with the activating KIR3DS1 receptor on NK cells, it triggers NK cell degranulation and the production of antiviral cytokines (Garcia-Beltran WF et al. 2016). Inhibits the effector functions of NK and T cells through interaction with the KIR3DL2 receptor (PubMed:24018270). Can interact with other MHC class I OCs to present exogenous viral, tumor or minor histocompatibility antigens to cytotoxic CD8+ T cells, triggering effector and memory responses (Garcia-Beltran WF et al. 2016). May play a role in inflammatory responses in the peripheral nervous system. Interaction with KIR3DL2 can protect motor neurons from astrocyte-induced toxicity (Goodridge JP et al. 2013).

This gene belongs to the HLA class I heavy chain paralogs. It encodes a non-classical heavy chain that forms a heterodimer with a light chain of beta-2-microglobulin, with the heavy chain anchored in the membrane. Unlike most other HLA heavy chains, this molecule is localized in the endoplasmic reticulum and Golgi apparatus, with a small amount present on the cell surface in some cell types. It contains a divergent peptide binding groove and is thought to bind a limited number of peptides for immune presentation. Diseases associated with HLA-F include nasopharyngeal carcinoma and gastric cancer.

1. Garcia-Beltran WF et al. (2016) Open conformers of HLA-F are high-affinity ligands of the activating NK-cell receptor KIR3DS1. Nat Immunol 17:1067-1074.
2. Goodridge JP et al. (2013) HLA-F and MHC class I open conformers are ligands for NK cell Ig-like receptors. J Immunol 191:3553-3562.
3. Kiani Z et al. (2019) HLA-F on Autologous HIV-Infected Cells Activates Primary NK Cells Expressing the Activating Killer Immunoglobulin-Like Receptor KIR3DS1. J Virol 93:e00933-19.