Immunobiology of HLA Class-Ib Molecules in Transplantation
Authors: Vadim Jucaud, Mepur H. Ravindranath, Paul I. Terasaki
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The objective of this review is to elucidate the role of HLA-Ib molecules in transplantation after elucidating their immunobiological potential. Structurally, the non-classical HLA-Ib molecules (HLA-E, HLA-F and HLA-G) are less polymorphic than HLA-Ia molecules. In transplantation, HLA-Ib molecules are emerging as immune regulators, functioning as ligands for immunomodulatory cell surface receptors expressed by the subsets of NK and CD8+ T cells-the major players in allograft rejection. HLA-E is the most pleiotropic molecule in an allograft setting; it can interact with both inhibitory (CD94/NKG2A) and activating (CD94/NKG2C) receptors expressed by NK and CD8+ T cells. This interaction is dependent on the nature and source of peptides presented by HLA-E. When HLA-Ia-derived peptides are presented, HLA-E interacts with CD94/NKG2A, inhibiting the cytotoxic cell functions that promote graft survival. When the HLA-G leader sequence is presented, it interacts mainly with CD94/NKG2C to activate the cytotoxic cells, leading to graft rejection. In addition, HLA-E can present viral and bacterial peptides that can bind to both CD94/NKG2 receptors, and also can interact with the other receptors of CD8+ cells, enhancing the risk of allograft rejection. HLA-G and HLA-F can promote graft acceptance by binding to another family of receptors: the Ig-like transcripts (ILT2/ ILT4) expressed by NK cells. Consequently, higher levels of HLA-G on the cell surface and in circulation promote graft acceptance, survival, and immunosuppression-free status for graft recipients. In contradistinction, overexpression of HLA-Ib results in higher risk of developing Graft-versus-Host Disease (GvHD) in cell transplantation. Soluble HLA-Ib (sHLA-Ib) molecules are augmented in circulation during injury, inflammation and transplantation. The sHLA-Ib can be free or associated with β2-microglobulin. In addition, sHLA-Ib molecules occur in a variety of conformations (isoform); as a result, HLA-Ib exposes epitopes to different immune components, contributing to antibody production. These antibodies can be monospecific or polyreactive. Binding of the monospecific antibodies can block the interaction of HLA-Ib with inhibitory receptors on cytotoxic cells, affecting graft survival. Polyreactive antibodies that bind to both cryptic and non-cryptic domains can affect routine HLAIa antibody screening and organ allocation. The antibodies binding to a cryptic domain are capable of suppressing blastogenesis and proliferation of CD4+ T cells as well as secretion of HLA antibodies by B cells; both could prolong graft survival.