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Recent Research Progress
The non-classical human leukocyte antigen-G (HLA-G), plays an important role in inducing tolerance, through its immuno-suppressive effects on all types of immune cells. Immune tolerance is a key issue in the liver, both in liver homeostasis and in the response to liver injury or cancer. Therefore, it would appear likely that HLA-G plays an important role in liver diseases. Indeed, this molecule was recently shown to be produced by mast cells in the livers of patients infected with hepatitis C virus (HCV). Furthermore, the number of HLA-G-positive mast cells was significantly associated with fibrosis progression.
In vitroexperiments have shown (Figure1) that HLA-G / sHLA-G molecules from transplanted patients or from isolated cultured cytotrophoblast cells produce short-term inhibition of T cells, NK cells and B cells by binding to immunoglobulin- like transcript receptor-2 (ILT2), immunoglobulin-like transcript receptor-4 (ILT4) and the killer immunoglobulin-like receptor 2DL4 (KIR2DL4). In all experimental settings, inhibition of HLA-G was eliminated in the presence of blocking antibodies specific for HLA-G. Interestingly, binding of HLA-G to ILT2 inhibits naive and memory B cell function. In particular, HLA-G is able to prevent B cell proliferation, differentiation and Ig secretion in a T cell-dependent and independent model of B cell activation. Furthermore, it appears that HLA-G acts as a negative B cell modulator in the regulation of B cell antibody secretion in a xenogeneic mouse model.
Figure 1. Induction of short- and long-term tolerance by HLA-G (Vera Rebmann, et al. 2014).
The indirect inhibition of HLA-G results in enhanced expression of ILT 2, ILT 3, ILT 4 and KIR2DL4 receptors in antigen presenting cells, NK cells and T cells. This upregulation does not seem to require any antigen co-stimulation. By up-regulating the inhibitory receptor, the immune activation threshold of the receptor effector cells can be increased, thereby achieving better graft acceptance. Another important indirect pathway is to induce HLA-E expression on the cell surface by providing HLA-G-specific leader peptides. The HLA-G leader peptide interacts with the inhibitory receptor complex CD94/NKG2A to prevent NK cell-dependent lysis. Finally, HLA-G-expressing cells regulate the ability of decidual mononuclear cells or peripheral blood mononuclear cells to store cytokines, thereby allowing Th1/Th2 balance to progress in a relative Th2 direction. In addition, the presence of sHLA-G molecules specifically stimulates the release of IL-10.
In addition to these short term effect, HLA-G can also provide long term inhibitory effect. The interaction of HLA-G with the ILT4 receptor can trigger this long-term effect. In mouse transplantation models, it has been shown that binding of ILT4 to HLA-G5 dimers or HLA-G1 tetrameric complexes (such as dendritic cells (DC)) on antigen presenting cells (APCs) inhibits their maturation, which results in no reactivity and reduces the expression of MHC class II, CD80 and CD86. Preliminary evidence suggests that bone marrow cells are also sensitive to HLA-G because they have ILT2 and ILT4 receptors expressed on the cell surface. In the ILT2 transgenic mouse model, HLA-G induces differentiation of bone marrow-derived suppressor cells and promotes long-term survival.
In summary, HLA-G is a highly tolerant molecule. Its immunosuppressive effect plays an important role in liver disease and transplantation, and has a negative impact on tumors, making it a new target for future treatment.