Revisiting HLA-G in solid organ transplantation: Mechanistic insights and translational advances

Human leukocyte antigen-G (HLA-G) is a non-classical MHC class I molecule with potent immunoregulatory functions that plays a central role in promoting allograft acceptance. Unlike classical HLA molecules, HLA-G displays limited polymorphism, restricted tissue distribution, and strong inhibitory signaling through receptors such as ILT-2, ILT-4, and KIR2DL4 on T cells, NK cells, B cells, dendritic cells, and myeloid populations. Across kidney, liver, heart, and lung transplantation, increased HLA-G expression-whether membrane-bound or soluble-consistently correlates with reduced acute rejection, lower alloimmune activation, and enhanced long-term graft survival. Recent multi-omics, structural, and mechanistic studies have expanded the HLA-G landscape by identifying alternative isoforms, including HLA-GΔα1 a naturally occurring variant lacking the α1 domain. Emerging evidence suggests that HLA-GΔα1 retains partial receptor-binding capacity and may uniquely modulate myeloid and regulatory cell networks. Therapeutic interest in HLA-G has rapidly grown, including in synthetic α3-domain peptides, recombinant HLA-G proteins, and HLA-G-expressing mesenchymal stem cell platforms that induce durable operational tolerance in preclinical models. This review synthesizes recent advances in HLA-G biology, its clinical relevance in solid organ transplantation, the evolving understanding of HLA-GΔα1 isoforms, and the translational strategies targeting this pathway to achieve stable, rejection-free graft function.