Conformational Alterations of the Cell Surface of Monomeric and Dimeric β2m-Free HLA-I (Proto-HLA) May Enable Novel Immune Functions in Health and Disease.

Human leukocyte antigens (HLAs) are polymorphic glycoproteins expressed on the cell surface of nucleated cells and consist of two classes, HLA class I and HLA class II. In contrast, in mice, these molecules, known as H-2, are expressed on both nucleated cells and erythrocytes. HLA-I molecules (Face-1) are heterodimers consisting of a polypeptide heavy chain (HC) and a light chain, B2-microglobulin (B2m). The heterodimers bind to antigenic peptides and present them to the T-cell receptors of CD8+ cytotoxic T lymphocytes. The HCs can also independently emerge on the cell surface as B2m-free HC monomers without peptides (Face-2). Early investigators suggested that the occurrence of B2m-free HCs on the cell surface resulted from the dissociation of B2m from Face-1. However, others documented the independent emergence of B2m-free HCs (Face-2) from the endoplasmic reticulum (ER) to the cell surface. The clustering of such HC molecules on either the cell surface or on exosomes resulted in the dimerization of B2m-free HCs to form homodimers (if the same allele, designated as Face-3) or heterodimers (if different alleles, designated as Face-4). Face-2 occurs at low levels on the cell surface of several normal cells but is upregulated on immune cells upon activation by proinflammatory cytokines and other agents such as anti-CD3 antibodies, phytohemagglutinin, and phorbol myristate acetate. Their density on the cell surface remains high as long as the cells remain activated. After activation-induced upregulation, Face-2 molecules undergo homo- and heterodimerization (Face-3 and Face-4). Observations made on the structural patterns of HCs and their dimerization in sharks, fishes, and tetrapod species suggest that the formation of B2m-free HC monomers and dimers is a recapitalization of a phylogenetically conserved event, befitting the term Proto-HLA for the B2m-free HCs. Spontaneous arthritis occurs in HLA-B27+ mice lacking B2m (HLA-B27+ B2m-/-) but not in HLA-B27+ B2m+/+ mice. Anti-HC-specific monoclonal antibodies (mAbs) delay disease development. Some HLA-I polyreactive mAbs (MEM series) used for immunostaining confirm the existence of B2m-free variants in several cancer cells. The conformational alterations that occur in the B2m-free HCs enable them to interact with several inhibitory and activating receptors of cellular components of the innate (natural killer (NK) cells) and adaptive (T and B cells) immune systems. The NK cells express killer immunoglobulin-like receptors (KIRs), whereas leukocytes (T and B lymphocytes, monocytes/macrophages, and dendritic cells) express leukocyte immunoglobulin-like receptors (LILRs). The KIRs and LILRs include activating and inhibitory members within their respective groups. This review focuses on the interaction of KIRs and LILRs with B2m-free HC monomers and dimers in patients with spondylarthritis. Several investigations reveal that the conformational alterations occurring in the alpha-1 and alpha-2 domains of B2m-free HCs may facilitate immunomodulation by their interaction with KIR and LILR receptors. This opens new avenues to immunotherapy of autoimmune diseases and even human cancers that express B2m-free HCs.