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.

Human Amnion Epithelial Cells Impair T Cell Proliferation: The Role of HLA-G and HLA-E Molecules

“…Since the mechanism(s) underlying these immunoregulatory properties of hAEC have been only partially elucidated [55], we focused on investigating the role of HLA-Ib molecules, particularly HLA-G. HLA-G can interact with different receptors, namely immunoglobulin-like transcript (ILT) 2, ILT4, KIR2DL4, CD160 and CD8α, which are differentially expressed on different cell populations. Upon interaction with these receptors, HLA-G can affect the function of immune effectors cells, leading to the suppression of the immune response in both physiological and pathological settings [33]. HLA-Ib molecules can bind peptides generated from the degradation of cytosolic proteins and present them to specific subpopulations of CD8+ T cells [20], like classical HLA-Ia molecules.…”

“…The HLA-F molecule can be expressed either associated with β2 microglobulin and peptides or as an open conformer (represented by heavy chain alone). These two different forms can bind to different receptors, triggering activating or inhibitory signals [33]. Few studies have previously described hAEC functions in relation to the release of extracellular vesicles (EVs) [34][35][36].…”

“…The HLA-F molecule can be expressed either associated with β2 microglobulin and peptides or as an open conformer (represented by heavy chain alone). These two different forms can bind to different receptors, triggering activating or inhibitory signals [ 33 ].…”

The Cynomolgus Macaque MHC Polymorphism in Experimental Medicine

“…The latter play a crucial role in the regulation of immune functions, and particularly in the activation of NK cells by their interaction with KIR and LILR receptors. The functional roles of these non-classical class I HLA proteins in the development of pregnancy, cancers, infectious diseases have recently been reviewed [157,158,159,160]. We have already indicated that the Mafa -E, Mafa -F genes, are found in all MHC macaque haplotypes and have low polymorphism, similarly to all other non-human primates.…”

A Natural Impact: NK Cells at the Intersection of Cancer and HIV Disease

“…The classical HLA-Ia group includes the highly polymorphic and ubiquitously expressed HLA-A, -B and -C antigens. Non-classical HLA-Ib antigens comprise HLA-E, -F, and -G molecules which are expressed in a tissue-specific manner, display low genetic diversity, and limited peptide repertoire (22). While the biological function and clinical relevance of most HLA-Ia and -Ib antigens have been investigated in detail, HLA-F was only recently recognized for its important immune-regulatory functions in cancer (23–26) and potentially in HIV infection (27).…”