Immunobiology of HLA Class-Ib Molecules in Transplantation

Abstract

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.