Figure 2 presents a timeline of the most representative achievements that contributed to the body of knowledge on the biology of open MHC-I conformers. This review critically analyzes past and recent advances that shed light on the non-immunological functions of cell surface MHC-I molecules and their implications in biomedicine. Forty-five years later, these hypotheses have been confirmed to a greater or lesser extent, unveiling an uncharted territory hidden for a long time behind the looking glass. In 1986, Michael Edidin summarized all these findings, including his own work with hormone receptors, and proposed that MHC-I molecules are likely part of functional hormone receptors and that their interactions modify the affinity of the receptors for their ligand. In 1985, Morten Simonsen and Lennart Olsson postulated that cell surface MHC-I molecules are a structural part of many receptors that they called compound receptors, with different biological functions. In 1977, Susumu Ohno suggested that the original role of cell surface MHC-I molecules was to serve as general anchorage sites of regulatory plasma membrane proteins involved in organogenesis and cell differentiation. In 1976, Arne Svejgaard and Lars Ryder proposed that HLA class I molecules may interfere with ligand–receptor interactions not involved in immune reactions, explaining the reported associations between HLA-I alleles and metabolic and neurobehaviour disorders. Thus, in the mid-1970s and 1980s, and as a result of experimental and clinical observations, farsighted scientists put forward four daring hypotheses. Figure 1 illustrates the typical structure of a cell surface closed MHC-I conformer.ĭespite their prominent role in peptide presentation to CD8+ T cells, studies carried out during the 1960s–1970s noticed that MHC-I genes and molecules were associated with non-immunological functions. Their primary function is immunological, namely to present peptides to CD8+ T cells and trans-interact with NK receptors. Accordingly, the trimeric MHC-I molecules present at the cell surface are also known as closed MHC-I conformers. In the ER, upon binding β2m and the peptide, the αHC folds into a closed/stabilized conformation.
MINERAL LOOKTHROUGH GLASS SERIES
Before being expressed at the plasma membrane, the three components of the MHC-I molecules assemble in the endoplasmic reticulum (ER) through a series of complex processes that have been extensively studied. While the α3 domain is conserved, the α1 and α2 domains are highly polymorphic and form a groove where the peptide binds. Seminal crystallographic studies revealed that the extracellular part of the αHC was organized into three domains: α1, α2, and α3. Biochemical and molecular biology studies revealed that human and mouse classical MHC-I molecules present at the plasma membrane are trimeric structures formed by a heavy chain of about 45 kDa (thereafter, αHC), non-covalently associated with a 12 kDa beta2-microglobulin light chain (thereafter, β2m), and an 8–12 amino acid peptide. They were initially identified as antigens involved in tissue rejection in mice and transfusion-related comorbidities in humans and, hence, called transplantation antigens.
MINERAL LOOKTHROUGH GLASS FULL
We review past and recent developments, strengthening the view that open conformers are multifunctional structures capable of fine-tuning cell signaling, growth, differentiation, and cell communication.Ĭlassical Major Histocompatibility Complex class I (MHC-I) molecules (HLA-A, HLA-B, and HLA-C in humans H-2D, H-2K, and H-2L in mice) have a long past full of ins and outs and untold stories. Nowadays, open conformers are viewed as functional cis-trans structures capable of establishing physical associations with themselves, with other surface receptors, and being shed into the extracellular milieu. Notably, most of these functions appear to rely on the presence in hematopoietic and non-hematopoietic cells of heavy chains not associated with β2m and the peptide at the plasma membrane these are known as open MHC-I conformers. The mounting body of evidence indicates that these non-immunological MHC-I functions impact clinical and biomedical settings, including autoimmune responses, tumor escape, transplantation, and neuronal development. These include cis–trans-interactions with inhibitory and activating KIR and LILR, and cis-interactions with receptors for hormones, growth factors, cytokines, and neurotransmitters. Studies carried out during the last few decades have consistently shown that cell surface MHC class I (MHC-I) molecules are endowed with functions unrelated with antigen presentation.
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