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.
Highlights
HLA-G is a non-classical HLA class I molecule
Further underlining the functional relevance of HLA-Gbearing extracellular vesicles (EVs) in cancer, a recent study demonstrated that (i) EVs released by renal cancer stem cells carry HLA-G with a HLA-G1 typical molecular weight, (ii) these HLA-G-bearing EVs impair the differentiation of monocytes to mature DCs, and (iii) the presence of these DCs reduces the T cell proliferation
It is well established that tumor cells, cytotrophoblast cells, and mesenchymal stem/stromal cells (MSCs) secret HLA-G-bearing EVs in addition to non-vesicular soluble HLA-G
Summary
HLA-G is a non-classical HLA class I molecule. It is a potent suppressive molecule that impairs effector functions of immune cells belonging to the innate and adaptive immune system. Based on the functionality of receptors and their expression profile, membrane-expressed and soluble forms of HLA-G molecules are involved in immune regulation in pregnancy, inflammation, and cancer. Tumor-derived EVs can stimulate immune suppression and tumor progression in different ways including the inhibition of tumor-specific T cell function and proliferation [77], the promotion of regulatory T cells subsets [78], and transfer of oncogenic receptors [61].
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