Biological Characteristics of HLA-G and Its Role in Solid Organ Transplantation

Abstract

Organ transplantation is a lifesaving option for patients with advanced diseases. Rejection is regarded as one of the most severe risk factors post-transplantation. A molecule that contributes to immune tolerance and resisting rejection is human leukocyte antigen (HLA)-G, which belongs to the non-classical major histocompatibility complex class (MHC) I family. HLA-G was originally found to play a role during pregnancy to maintain immune tolerance between mother and child. It is expressed in the placenta and detected in several body fluids as soluble factor as well as different membrane isoforms on cells. Recent findings on HLA-G show that it can also play multifaceted roles during transplantation. This review will explain the general characteristics and biological function of HLA-G and summarize the views supporting the tolerogenic and other roles of HLA-G to better understand its role in solid organ transplantation (SOT) and its complications. Finally, we will discuss potential future research on the role of HLA-G in prevention, diagnosis, and treatment in SOT.

Keywords: HLA-G; immune regulation; immunosuppressive treatment; leukocyte immunoglobulin-like receptor; organ transplantation; polymorphisms; rejection.

Figure 1

the HLA-G molecule. (A): Schematic overview of the HLA-G isoforms. HLA-G1 to G4 are membrane bound isoforms and HLA-G5 to G7 are soluble isoforms, they are generated by alternative splicing. HLA-G1 and G5 complex contain α1 (red color), α2 (yellow color), and α3 (blue color) globular domains non-covalently associated with β2-microglobulin (black color). (B): 3D crystal structure of HLA-G (reproduced from Protein Data Bank (Gene ID: 1YDP) with permission. The heavy chain (hc) is shown in green, β2M in red, and the peptide in blue color. (C): HLA-G gene structure. Exon 1 encodes the signal peptide. Exons 2, 3, and 4 encode the α1, α2, and α3 domains, respectively. Exons 5 and 6 for the transmembrane (TM) and cytoplasmic (CT) domains, respectively. Exon 7 and exon 8 are not translated.

Figure 2

HLA-G immune inhibition by interaction with receptors on effector cells. sHLA-G and membrane bound HLA-G molecules interact with the ILT-2 and ILT-4 receptor on T, NK, B cells and macrophages resulting in the inhibition of cytotoxicity, proliferation, or antibody production. The interaction of HLA-G with CD8 coreceptor on certain T and NK cell population leads to the deletion of these cells. Long-term tolerance will be achieved by the induction of different types of regulatory T (Treg) cells. HLA-G and KIR2DL4 interaction on mast cells suppresses mediation of allergic reactions.

Figure 3

The role of HLA-G in controlling rejection in organ transplantation. The complex process involves both innate and adaptive immunity. HLA-G interaction on macrophages, monocytes, and NK cells can trigger the production of cytokines leading the inflammation contributes to rejection. Another interaction work on adaptive immunity involved direct and indirect pathways. The direct pathway is HLA-G directly inhibiting immune effectors such as T cells, B cells, and Natural Killer (NK) cells. The indirect pathway involves HLA-G acting on dendritic cells (DC) and CD8+/CD4+ T cells. Subsequently acting on T regulatory cell (T reg) formation, then continue acting on the direct pathway with inhibiting the functional cells.