Abstract
The human leukocyte antigen (HLA)-Ib molecule, HLA-F, is known as a CD4+ T-cell protein and mediator of HIV progression. While HLA-Ia molecules do not have the chance to select and present viral peptides for immune recognition due to protein downregulation, HLA-F is upregulated. Post HIV infection, HLA-F loses the affinity to its activating receptor KIR3DS1 on NK cells leading to progression of the HIV infection. Several studies aimed to solve the question of the biophysical interface between HLA ligands and their cognate receptors. It became clear that even an invariant HLA molecule can be structurally modified by the variability of the bound peptide. We recently discovered the ability of HLA-F to select and present peptides and the HLA-F allele-specific peptide selection from the proteomic content using soluble HLA (sHLA) technology and a sophisticated MS method. We established recombinant K562 cells that express membrane-bound HLA-F*01:01, 01:03 or 01:04 complexes. While a recombinant soluble form of KIR3DS1 did not bind to the peptide-HLA-F complexes, acid elution of the peptides resulted in the presentation of HLA-F open conformers, and the binding of the soluble KIR3DS1 receptor increased. We used CD4+/HIV− and CD4+/HIV+ cells and performed an MS proteome analysis. We could detect hemoglobin as significantly upregulated in CD4+ T-cells post HIV infection. The expression of cellular hemoglobin in nonerythroid cells has been described, yet HLA-Ib presentation of hemoglobin-derived peptides is novel. Peptide sequence analysis from HLA-F allelic variants featured hemoglobin peptides as dominant and shared. The reciprocal experiment of binding hemoglobin peptide fractions to the HLA-F open conformers resulted in significantly diminished receptor recognition. These results underpin the molecular involvement of HLA-F and its designated peptide ligand in HIV immune escape.
Highlights
The human leukocyte antigen F (HLA-F) is one of the non-classical HLA-Ib molecules (HLA-F, HLA-E and HLA-G)
We recently discovered the ability of HLA-F to select and present peptides and the HLA-F allele-specific peptide selection from the proteomic content using soluble HLA technology and a sophisticated MS method
While a recombinant soluble form of KIR3DS1 did not bind to the peptide-HLA-F complexes, acid elution of the peptides resulted in the presentation of HLA-F open conformers, and the binding of the soluble KIR3DS1 receptor increased
Summary
The human leukocyte antigen F (HLA-F) is one of the non-classical HLA-Ib molecules (HLA-F, HLA-E and HLA-G). The expression pattern of HLA-F is highly restricted and differs significantly from the classical HLA Ia (HLA-Ia) molecules. Surface expression of HLA-F has only been detected on. HLA-F OC constitutes the ligand for NK cell receptors such as killer immunoglobulin-like receptor (KIR) 3DS1 (KIR3DS1), KIR3DL1 and KIR3DL2 [4,5]. It has been assumed that HLA-F is entirely unable to present peptides [3], implying HLA-F to display an invariant surface for its cognate receptor. It has been demonstrated that HLA-F is able to assemble with β2m and to bind and present peptides like classical HLA-I molecules [6,7]. Peptide-HLA-F complexes (pHLA-F) are ligands for immunoglobulin-like transcript receptor-2 (ILT-2) [6,9]. HLA-F has the capability to impair NK cell reaction in both an inhibitory and activating way
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