Dimorphism of HLA-E and Its Disease Association

Abstract

HLA-E is a nonclassical member of the major histocompatibility complex class I gene locus. HLA-E protein shares a high level of homology with MHC Ia classical proteins: it has similar tertiary structure, associates with β2-microglobulin, and is able to present peptides to cytotoxic lymphocytes. The main function of HLA-E under normal conditions is to present peptides derived from the leader sequences of classical HLA class I proteins, thus serving for monitoring of expression of these molecules performed by cytotoxic lymphocytes. However, opposite to multiallelic classical MHC I genes, HLA-E in fact has only two alleles—HLA-E*01:01 and HLA-E*01:03—which differ by one nonsynonymous amino acid substitution at position 107, resulting in an arginine in HLA-E*01:01 (HLA-ER) and glycine in HLA-E*01:03 (HLA-EG). In contrast to HLA-ER, HLA-EG has higher affinity to peptide, higher surface expression, and higher thermal stability of the corresponding protein, and it is more ancient than HLA-ER, though both alleles are presented in human populations in nearly equal frequencies. In the current review, we aimed to uncover the reason of the expansion of the younger allele, HLA-ER, by analysis of associations of both HLA-E alleles with a number of diseases, including viral and bacterial infections, cancer, and autoimmune disorders.

Surface NKG2C Identifies Differentiated αβT-Cell Clones Expanded in Peripheral Blood

“…In our experimental system, no pp65-specific functional response was detected in the NKG2C-expressing part of the dominant clone. Presumably, the expansion of T cell clones that do not recognize the standard viral peptides in the context of MHC I occurs due to interaction of certain TCRs with HLA-E in the presence of UL40-derived peptides, as it happens in the case of NK cells due to NKG2C-HLA-E interaction ( 75 ). Despite a number of publications indicating the existence of HLA-E-restricted T cells, the role of NKG2C receptor in the recognition of and interaction with HLA-E molecule bearing viral peptides remains intriguing.…”

Peptide Binding to HLA-E Molecules in Humans, Nonhuman Primates, and Mice Reveals Unique Binding Peptides but Remarkably Conserved Anchor Residues

“…Despite both HLA-E alleles being equally prevalent in the human population (45,46), HLA-E*01:01 and HLA-E*01:03 homozygosity have been associated with increased risk to or protection from infections, cancer, and autoimmune disorders, suggesting distinct roles in certain pathological conditions (47). Differences in peptide binding and surface stability, which may lead to functional differences between HLA-E*01:01 and HLA-E*01:03, support the importance of defining peptide binding motifs to each human HLA-E molecule (31,48,49).…”

Identification of Immunological Parameters as Predictive Biomarkers of Relapse in Patients with Chronic Myeloid Leukemia on Treatment-Free Remission

“…HLA-E*0103 has been associated with higher susceptibility to cancer diseases such as acute leukemia [ 64 ] and ovarian cancer [ 65 ], as well as with an increased risk of mortality in patients with chronic lymphocytic leukemia [ 66 ]. However, no association between cancer and HLA-E*0101 has been reported so far [ 67 ]. Both alleles differ only in one amino acid (Arg107Gly) that leads to higher stability of HLA-E*0103 on the cell surface, which increases half-life and prolongs the interaction with immune effector cells [ 68 ].…”

“…Therefore, the beneficial role of HLA-E*0101 for avoiding relapse of CML could be related to its decreased expression on the cell surface, which could result in lower inhibitory activity of NKG2A+ cells [ 70 ], and to a less restrictive peptide repertoire presentation than that found with HLA-E*0103 [ 71 ]. Furthermore, HLA-E*0103 allele has been associated with high levels of soluble HLA-E (sHLA-E), which provides protection against NK-mediated lysis [ 72 ] and usually correlates with disorders such as cancer and autoimmune diseases [ 67 ]. To our knowledge, this is the first report that describes a possible association between higher susceptibility to CML relapse and HLA-E*0103 homozygosis, which highlights the usefulness of this allele as biomarker.…”