Human Leukocyte Antigen F Presents Peptides and Regulates Immunity through Interactions with NK Cell Receptors

Abstract

Summary Evidence is mounting that the major histocompatibility complex (MHC) molecule HLA-F regulates the immune system in pregnancy, infection, and autoimmunity by signaling through NK-cell receptors (NKRs). We present structural, biochemical and evolutionary analyses demonstrating that HLA-F presents peptides of unconventional length dictated by a newly arisen mutation (R62W) that has produced an open-ended groove accommodating particularly long peptides. Compared to empty HLA-F open conformers (OC), HLA-F tetramers bound with human-derived peptides differentially stained leukocytes suggesting peptide-dependent engagement. Our in vitro studies confirm that NKRs differentiate between peptide-bound and peptide-free HLA-F. The complex structure of peptide-loaded β2m-HLA-F bound to the inhibitory LIR1 revealed similarities to high-affinity recognition of the viral MHC-I mimic UL18 and a docking strategy that relies on contacts with HLA-F as well as β2m, thus precluding binding to HLA-F OC. These findings provide a biochemical framework to understand how HLA-F could regulate immunity via interactions with NKRs.

An ancient fecundability-associated polymorphism creates a new GATA2 binding site in a distal enhancer ofHLA-F

“…While the precise functions of HLA-F are unclear, our observations that its expression level in the endometrium during the window of implantation is associated with fecundability 6 , and that it is up-regulated by progesterone implicates it in the establishment of pregnancy. Intriguingly HLA-F binds LIR and KIR natural killer cell receptors [13][14][15][16][17] , suggesting HLA-F expressed by DSCs directly signal to uterine natural killer (uNK) cells which are essential for the establishment of maternal immunotolerance and spiral artery remodeling. Consistent with this hypothesis HLA-F expression level is positively correlated with uNK abundance in mid-luteal endometria and is predictive of achieving pregnancy 6,18 .…”

“…Furthermore HLA-F expression increases during gestation, reaching a peak at term 9,12 . Like other MHC-I molecules, HLA-F binds natural killer (NK) cell receptors from the LIR and KIR families, including LIR1 and LIR2 13,14 , KIR2DS4 and KIR3DL2 15 , and KIR3DL1 and KIR3DS1 14,16,17 . Uterine natural killer (uNK) cells, which are essential for the establishment and maintenance of maternal immunotolerance and spiral artery remodeling, express KIR3DL1 and LIR2 suggesting HLA-F expressed by EVTs and DSCs mediate interactions with uNK during implantation, trophoblast invasion, and establishment of the uteroplacental circulation.…”

Killer‐cell immunoglobulin‐like receptor assessment algorithms in haemopoietic progenitor cell transplantation: current perspectives and future opportunities

“…The relationship between inhibitory KIR and HLA class I proteins is well characterised, but the ligands of activating KIR genes remain largely elusive. KIR3DS1 has been shown to exhibit affinity for HLA Bw4 and HLA‐F (a non‐classical HLA class I molecule), and KIR2DS1 binds the C2 epitope . Evidence has indicated that KIR3DS1 binds to the HLA‐B*57:01 protein/peptide complex in a peptide‐dependent manner (an HLA allotype which contains the HLA‐Bw4 epitope), suggesting that in some cases the presentation of the cognate peptide within the HLA molecule's peptide binding groove is necessary to form a discontinuous epitope for KIR recognition .…”

Broad and thematic remodeling of the surface glycoproteome on isogenic cells transformed with driving proliferative oncogenes

“…NT5E, which was upregulated in all MAPK mutants, promotes immunosuppression through the production of adenosine from AMP, which can decrease the capacity of natural killer cells to produce immune activating IFN molecules and prevents the clonal expansion of cytotoxic T cells in the surrounding tumor tissue (Gao et al, 2014). Conversely, HLA-F and DSE (also known as dermatan sulfate epimerase), were downregulated in all oncogene expressing cell lines, and both play a role in immune system activation and tumor-rejection, through activation of NK cells or cytotoxic T cells, respectively, in the tumor microenvironment (Dulberger et al, 2017;Liao et al, 2019). Both NT5E and HLA-F show reversed expression levels upon…”

“…However, we do not know how expression of different oncogenes globally alters glycosylation on individual proteins at a proteome-wide scale. Very recently, hybrid type ETD methods, such as activated ion electron transfer dissociation (AI-ETD) and ETD with supplemental activation (EThcD), have emerged as forerunners for glycoproteomic profiling due to their ability to generate sequence informative tandem mass spectra that links both the peptide backbone and corresponding glycan modification (Liu et al, 2017;Riley et al, 2019;Yang et al, 2017).…”