The Potential of HLA-G-Bearing Extracellular Vesicles as a Future Element in HLA-G Immune Biology

Abstract

The HLA-G molecule is a member of the non-classical HLA class I family. Its surface expression is physiologically restricted to the maternal–fetal interface and to immune privileged adult tissues. Despite the restricted tissue expression, HLA-G is detectable in body fluids as secreted soluble molecules. A unique feature of HLA-G is the structural diversity as surface expressed and as secreted molecules. Secreted HLA-G can be found in various body fluids either as free soluble HLA-G or as part of extracellular vesicles (EVs), which are composed of various antigens/ligands/receptors, bioactive lipids, cytokines, growth factors, and genetic information, such as mRNA and microRNA. Functionally, HLA-G and its secreted forms are considered to play a crucial role in the network of immune-regulatory tolerance mechanisms, preferentially interacting with the cognate inhibitory receptors LILRB1 and LILRB2. The HLA-G mediated tolerance is described in processes of pregnancy, inflammation, and cancer. However, almost all functional and clinical implications of HLA-G in vivo and in vitro have been established based on simple single ligand/receptor interactions at the cell surface, whereas HLA-G-bearing EVs were in minor research focus. Indeed, cytotrophoblast cells, mesenchymal stem cells, and cancer cells were recently described to secrete HLA-G-bearing EVs, displaying immunosuppressive effects and modulating the tumor microenvironment. However, numerous functional and clinical open questions persist. Here, we (i) introduce basic aspects of EVs biology, (ii) summarize the functional knowledge, clinical implications and open questions of HLA-G-bearing EVs, and (iii) discuss HLA-G-bearing EVs as a future element in HLA-G biology.

Immunosuppressive role of extracellular vesicles: HLA-G, an important player

“…In this contest, EVs may act in concert with several soluble factors such as PGE 2 , IDO and HLA-G (6). The important role of HLA-G and EVs was well described in a recent review (7). In this paper, the authors clearly describe the function of the secreted form of HLA-G within EVs, compared with the free soluble fraction.…”

“…In this paper, the authors clearly describe the function of the secreted form of HLA-G within EVs, compared with the free soluble fraction. The secreted forms of HLA-G are mainly involved in immune tolerance in cancer and pregnancy (7). However, most of the studies do not discriminate the free soluble form from the EV associated HLA-G.…”

“…There are seven isoforms. The isoforms HLA-G1, G2, G3 and G4 are transmembrane while the isoforms G5, G6 and G7 lack the transmembrane domains and are soluble (7,8). In addition, all the membrane-expressed isoforms may be cleaved by metalloprotease enzymes and became soluble (9).…”

The discovery of HLA-G-bearing extracellular vesicles: new perspectives in HLA-G biology

“…This study highlighted the critical importance of defining the presence of HLA-G free or EVs-linked and how these two molecules may have opposite impact on disease progression, as they may promote immune escape or not. Based on this first demonstration, Rebmann et al (15) discussed and proposed in their perspective the importance to discriminate the source of the different forms of soluble HLA-G, free or EV-linked, present in plasma or in serum of patients to better define their contribution in cancer, and, therefore, their use as biomarker of disease stage, progression, or response to therapy.…”

“…Rebmann et al (15) also highlighted the consequences of the discovery of HLA-G-bearing EVs in the biology of HLA-G. In this contest, it has to be taken into account that EV-linked HLA-G can be expressed either as membrane-bound or as soluble form within the vesicles.…”