The Emerging Roles of Human Leukocyte Antigen-F in Immune Modulation and Viral Infection

Abstract

Human leukocyte antigens (HLAs) play various critical roles in both innate and adaptive immunity through processes such as presenting antigens to T cells and serving as ligands for receptors expressed on natural killer (NK) cells. Among the HLA class I family, the clinical significance and biological function of HLA-F have been the least investigated and have remained elusive for a long period of time. Previous studies have revealed that HLA-F expression might be involved in various physiological and pathological processes, such as pregnancy, viral infection, cancer, transplantation, and autoimmune diseases. However, recent data have shown that, akin to other HLA family members, HLA-F molecules can interact with both activating and inhibitory receptors on immune cells, such as NK cells, and can present a diverse panel of peptides. These important findings pave new avenues for investigations regarding the functions of HLA-F as an important immune regulatory molecule. In the present review, we summarize the studies on the role of HLA-F in immune modulation, with a special emphasis placed on the roles of HLA-F and KIR3DS1 interactions in viral infection.

Keywords: human leukocyte antigen F; immune cells; immune regulation; receptor; viral infection.

Figure 1

Immune receptors for the human leukocyte antigen (HLA-F) open conformer (OC) and HLA-F:peptide:β₂m complex. (A) HLA-F OCs can be recognized with the highest affinity by the activating receptor KIR3DS1 and can be recognized by the inhibitory receptors KIR3DL1/2. However, the results regarding the interaction of the HLA-F OC and the activating receptor KIR2DS4 are disputed (27, 28, 30, 31). (B) The HLA-F:peptide:β₂m complex can only be recognized by the inhibitory receptors immunoglobulin (Ig)-like transcript receptor 2 (ILT2) and ILT4 (29, 30). However, whether there are HLA-F peptide-restricted T cell receptors (TCRs) is not yet known (30). (C) HLA-I OCs can be expressed on the cell surface as homodimers (43), and it has been postulated that HLA-I/HLA-F heterodimers can form (44). Whether HLA-F can be recognized by other TCRs or natural killer cell receptors (NCRs) remains to be explored. Killer cell immunoglobulin-like receptors (KIRs) are transmembrane glycoproteins expressed on natural killer (NK) cells and on subpopulations of T cells. KIRs have either two (2D) or three (3D) extracellular immunoglobulin (Ig)-like domains and different cytoplasmic tails (short or long). Inhibitory KIRs have long cytoplasmic tails (L) that contain immunoreceptor tyrosine-based inhibition motifs (ITIMs). Activating KIRs have short cytoplasmic tails (S) that lack ITIMs but associate with the immunoreceptor tyrosine-based activation motif (ITAM), such as the adapter DAP12, via a positively charged arginine or lysine residue in their transmembrane domain. Immunoglobulin-like transcript 2 (ILT2, also known as CD85j and LIR1) has four extracellular Ig-like domains and four cytoplasmic ITIMs. ILT4 (also known as CD85d and LIR2) has four extracellular Ig-like domains and three cytoplasmic ITIMs. TCRs (T cell receptors) recognize peptides presented by HLA molecules.