HLA-G/ILT2 signaling on the path to tolerance

Practitioners of thoracic transplantation note with jealousy how select liver transplant recipients develop an operational tolerance, permitting complete withdrawal of immunosuppression. This tolerance relies on multiple mechanisms to stem alloimmune responses, including enhanced regulatory T cell function, innate lymphoid cell deletion of effector T cells, suppression of toll-like receptor-signaling, immunosuppressive macrophage functions, diminished co-stimulation, and lymphocyte inhibitory molecules. 1 Toti L Manzia TM Sensi B et al. Towards tolerance in liver transplantation. Best Pract Res Clin Gastroenterol. 2021; 54-55101770 Crossref PubMed Scopus (1) Google Scholar Hope for operational tolerance in thoracic transplantation rests on a such multifaceted suppression of immune activation, and human leukocyte antigen G (HLA-G) is one molecule of interest for its innate potential to drive tolerance. This nonclassical major histocompatibility complex class I molecule was originally discovered in maternal-fetal tolerance, where its expression on the extravillous cytotrophoblast protects from attack by the maternal immune system. 2 Ferreira LMR Meissner TB Tilburgs T Strominger JL. HLA-G: at the interface of maternal-fetal tolerance. Trends Immunol. 2017; 38: 272-286 Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar HLA-G binds to 3 inhibitory receptors: (1) immunoglobulin-like transcript 2 (ILT2), which is also known as leukocyte immunoglobulin-like receptor subfamily B1 or CD85j and expressed by human T cells, B cells, natural killer cells, monocytes, and dendritic cells; (2) the myeloid-specific ILT4 (LILRB2/CD85d) receptor; and (3) the killer immunoglobulin-like receptor 2DL4 (KIR2DL4/CD158d), which is mainly expressed on decidual natural killer cells. HLA-G can have immune suppressive effects whether bound to the cell surface, secreted in soluble form, or intracellularly in endosomes. 2 Ferreira LMR Meissner TB Tilburgs T Strominger JL. HLA-G: at the interface of maternal-fetal tolerance. Trends Immunol. 2017; 38: 272-286 Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar Polymorphisms resulting in decreased HLA-G expression are associated with pregnancy complications. At the same time tumor cells can co-opt this pathway, expressing high levels of HLA-G to avoid immune surveillance.