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

In contrast to classical human histocompatibility antigen (HLA) class I molecules, HLA-G has been discovered quite recently, in 1990. Since its discovery several efforts have been made to define HLA-G biology and its role in regulating immune responses. The main distinctive characteristics of HLA-G are the limited protein variability, alternative mRNA splicing that generates seven different isoforms(both soluble and membrane-bound) with the ability to form multiple structures via disulfide bounds, and restricted expression to certain tissues (1). Moreover, the discovery that HLA-G binds different inhibitory receptors (i.e., ILT2 and ILT4, and KIR2DL4) led to the classification of HLA-G as a tolerogenic molecule (2).