Mammalian non-classical major histocompatibility complex I and its receptors: Important contexts of gene, evolution, and immunity

Abstract

The evolutionary conserved, less-polymorphic, nonclassical major histocompatibility complex (MHC) class I molecules: Qa-1 and its human homologue human leukocyte antigen-E (HLA-E) along with HLA-F, G and H cross-talk with the T-cell receptors and also interact with natural killer T-cells and other lymphocytes. Moreover, these nonclassical MHC molecules are known to interact with CD94/NKG2 heterodimeric receptors to induce immune responses and immune regulations. This dual role of Qa-1/HLA-E in terms of innate and adaptive immunity makes them more interesting. This review highlights the new updates of the mammalian nonclassical MHC-I molecules in terms of their gene organization, evolutionary perspective and their role in immunity.

Classical and non-classical HLA class I aberrations in primary cervical squamous- and adenocarcinomas and paired lymph node metastases

“…These molecules are responsible for tumor-associated antigen presentation at the cell surface for recognition by cytotoxic T cells (CTLs) and targeted cell lysis [2–6]. In addition, tumor cells are able to increase the expression of non-classical HLA class I molecules (HLA-E and HLA-G), which can interact with the inhibitory receptors CD94/NKG2A and KIR2DL4/p49 on natural killer (NK) cells, as well as on effector T cells and myeloid cells (e.g., ILT2 and ILT4), leading to decreased NK cell and/or T cell effector activity and hereby potential tumor progression [7–11]. However, it has also been reported that KIR2DL4 can act as a stimulatory molecule [12].…”

HLA-H: Transcriptional Activity and HLA-E Mobilization

“…In different clinical studies, the HLA-G * 01:04 haplotype, in which HLA-H was deleted, was associated with an impaired outcome (22,38,39). The full-length HLA-H protein showed similar domains to non-classical class I molecules (10), HLA-G, -E, and -F, molecules, which displayed immune response activation and inhibition (15)(16)(17)(18)(19)(20)(21). Furthermore, the HLA-H signal peptide (MVLMAPRTLLLLLSGALALTQTWA) was almost identical to that of HLA-A (MAVMAPRTLLLLLSGALALTQTWA), except that there was a Valine in the second position as in HLA-G (MVVMAPRTLFLLLSGALTLTETWA), and there was a specific amino acid (Val>Leu) in the third position, compared to other HLA class I proteins (40).…”

“…Physiologically, HLA-E is expressed at the surface of endothelial cells, T and B lymphocytes, monocytes, and macrophages (41). However, HLA-E, transcribed in most tissues (24), can be mobilized to the cell surface by different peptides, such as stress protein peptides and peptides derived from different pathogens (16,18). We thus performed assays in PBMC, as described in (37), as well as in primary epithelial cells.…”

“…Like the non-classical class I molecules, HLA-G, -E, and -F, which display immune response activation and inhibition (15)(16)(17)(18)(19)(20)(21) HLA-H may be tolerogenic and participate in immune homeostasis. In cases where the immune system is challenged, the absence of HLA-H might lessen tolerogenicity; in Lung Transplant patients (LTx), the HLA-G * 01:04 allele, in Linkage Disequilibrium (LD) with HLA-H * deletion, was associated with impaired long-term survival, increased Chronic Lung Allograft Dysfunction (CLAD) occurrence, and the production of de novo Donor Specific Antigen (DSA) (22).…”

“…HLA-H may act like HLA-G, -E, and -F, both directly as a transmembrane molecule and/or indirectly via its signal peptide by mobilizing HLA-E to the cell surface. HLA-E, which regulates NK and cytotoxic T-lymphocyte cells via the inhibitory receptor CD94/NKG2 (16,18,19), is transcribed in most tissues (24) but is mobilized to the cell surface by signal peptides from HLA Ia, HLA-G, and peptide ligands from stress proteins and viruses (25,26).…”