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Non-classical major histocompatibility complex proteins as determinants of tumour immunosurveillance.

ABSTRACT: Tumours develop in vertebrate organisms endowed with immune systems that are potentially able to eradicate them. Nevertheless, our ever-increasing understanding of the complex interactions between lymphocytes and tumour cells fuels the long-standing hope of developing efficient immunotherapies against cancer. This review focuses on a versatile family of proteins, the major histocompatibility complex class Ib, which has been recently implicated in both the establishment of anti-tumour immune responses and in tumour immune response evasion. We focus on a subset of class Ib proteins, human leukocyte antigen (HLA)-G, Qa-2, CD1d and NKG2D ligands, which bind to either stimulatory or inhibitory receptors expressed on T, natural killer (NK) and NKT lymphocytes, and thereby modulate their anti-tumour activity.

SUBMITTER: Gomes AQ

PROVIDER: S-EPMC2247375 | biostudies-other | 2007 Nov

REPOSITORIES: biostudies-other

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Structure and function of the non-classical major histocompatibility complex molecule MR1.

Project description:Polymorphic major histocompatibility complex (MHC) molecules play a central role in the vertebrate adaptive immune system. By presenting short peptides derived from pathogen-derived proteins, these "classical" MHC molecules can alert the T cell branch of the immune system of infected cells and clear the pathogen. There exist other "non-classical" MHC molecules, which while similar in structure to classical MHC proteins, are contrasted by their limited polymorphism. While the functions of many class Ib MHC molecules have still to be elucidated, the nature and diversity of antigens (if any) that some of them might present to the immune system is expected to be more restricted and might function as another approach to distinguish self from non-self. The MHC-related 1 (MR1) molecule is a member of this family of non-classical MHC proteins. It was recently shown to present unique antigens in the form of vitamin metabolites found in certain microbes. MR1 is strongly conserved genetically, structurally, and functionally through mammalian evolution, indicating its necessity in ensuring an effective immune system for members of this class. Although MR1 will be celebrating 21 years this year since its discovery, most of our understanding of how this molecule functions has only been uncovered in the past decade. Herein, we discuss where MR1 is expressed, how it selectively is able to bind to its appropriate antigens and how it, then, is able to specifically activate a distinct population of T cells.

| S-EPMC5091073 | biostudies-literature

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

Project description: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.

| S-EPMC4228563 | biostudies-literature

The non-classical major histocompatibility complex II protein SLA-DM is crucial for African swine fever virus replication.

Project description:African swine fever virus (ASFV) is a lethal animal pathogen that enters its host cells through endocytosis. So far, host factors specifically required for ASFV replication have been barely identified. In this study a genome-wide CRISPR/Cas9 knockout screen in porcine cells indicated that the genes RFXANK, RFXAP, SLA-DMA, SLA-DMB, and CIITA are important for productive ASFV infection. The proteins encoded by these genes belong to the major histocompatibility complex II (MHC II), or swine leucocyte antigen complex II (SLA II). RFXAP and CIITA are MHC II-specific transcription factors, whereas SLA-DMA/B are subunits of the non-classical MHC II molecule SLA-DM. Targeted knockout of either of these genes led to severe replication defects of different ASFV isolates, reflected by substantially reduced plating efficiency, cell-to-cell spread, progeny virus titers and viral DNA replication. Transgene-based reconstitution of SLA-DMA/B fully restored the replication capacity demonstrating that SLA-DM, which resides in late endosomes, plays a crucial role during early steps of ASFV infection.

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Classical major histocompatibility complex class I molecules in motoneurons: new actors at the neuromuscular junction.

Project description:Major histocompatibility complex (MHC) class I molecules have fundamental functions in the immune system. Recent studies have suggested that these molecules may also have non-immune functions in the nervous system, in particular related to synaptic function and plasticity. Because adult motoneurons express mRNAs for MHC class I molecules, we have examined their subcellular expression pattern in vivo and their role for the synaptic connectivity of these neurons. We observed immunoreactivity for classical MHC class I (Ia) protein in motoneuron somata, but the predominant expression was found in axons and presynaptically at neuromuscular junctions (NMJs). Peripheral nerve lesion induced a strong increase of motoneuron MHC class Ia (H2-K(b)/D(b)) mRNA, indicating a role for MHC class Ia molecules during regeneration. Accordingly, there was an accumulation of MHC class Ia proteins at the cut ends and in growth cones of motor axons after lesion. In K(b-/-)D(b-/-) mice (lacking MHC class Ia molecules), the time course for recovery of grip ability in reinnervated muscles was significantly delayed. Muscles from K(b-/-)D(b-/-) mice displayed an increased density and a disturbed distribution of NMJs and fewer terminal Schwann cells/NMJ compared with wild-type mice. A population of Schwann cells in sciatic nerves expressed the paired Ig receptor B, which binds to MHC class I molecules. These results provide the first evidence that neuronal MHC class Ia molecules are present in motor axons, that they are important for organization of NMJs and motor recovery after nerve lesion, and that their actions may be mediated via Schwann cells.

| S-EPMC6665011 | biostudies-literature

major histocompatibility complex class II

Project description:amphibian MHC IIB1 Raw sequence reads

| PRJNA862637 | ENA

The non-classical major-histocompatibility-complex II protein SLA-DM is crucial for African swine fever virus replication

Project description:African swine fever virus (ASFV) is a lethal animal pathogen which enters its host cells through endocytosis. So far, host factors specifically required for ASFV replication have been barely identified. In this study a genome-wide CRISPR/Cas9 knockout screen in porcine cells indicated that the genes RFXANK, RFXAP, SLA-DMA, SLA-DMB, and CIITA are important for productive ASFV infection. The proteins encoded by these genes belong to the major-histocompatibility-complex II (MHC II), or swine-leucocyte-antigen-complex II (SLA II). RFXAP and CIITA are MHC II-specific transcription factors, whereas SLA-DMA/B are subunits of the non-classical MHC II molecule SLA-DM. Targeted knockout of either of these genes led to severe replication defects of different ASFV isolates, reflected by substantially reduced plating efficiency, cell-to-cell spread, and progeny virus titers. For the characterization of the knockouts on a proteome level the protein contents of the knockout cell lines were analyzed by mass spectrometry.

2023-08-21 | PXD034242 | Pride

Inhibition of major histocompatibility complex-I antigen presentation by sarbecovirus ORF7a proteins.

Project description:Viruses employ a variety of strategies to escape or counteract immune responses, including depletion of cell surface major histocompatibility complex class I (MHC-I), that would ordinarily present viral peptides to CD8+ cytotoxic T cells. As part of a screen to elucidate biological activities associated with individual SARS-CoV-2 viral proteins, we found that ORF7a reduced cell surface MHC-I levels by approximately 5-fold. Nevertheless, in cells infected with SARS-CoV-2, surface MHC-I levels were reduced even in the absence of ORF7a, suggesting additional mechanisms of MHC-I downregulation. ORF7a proteins from a sample of sarbecoviruses varied in their ability to induce MHC-I downregulation and, unlike SARS-CoV-2, the ORF7a protein from SARS-CoV lacked MHC-I downregulating activity. A single-amino acid at position 59 (T/F) that is variable among sarbecovirus ORF7a proteins governed the difference in MHC-I downregulating activity. SARS-CoV-2 ORF7a physically associated with the MHC-I heavy chain and inhibited the presentation of expressed antigen to CD8+ T-cells. Speficially, ORF7a prevented the assembly of the MHC-I peptide loading complex and causing retention of MHC-I in the endoplasmic reticulum. The differential ability of ORF7a proteins to function in this way might affect sarbecovirus dissemination and persistence in human populations, particularly those with infection- or vaccine-elicited immunity.

| S-EPMC9164438 | biostudies-literature

?? T cell receptors recognize the non-classical major histocompatibility complex (MHC) molecule T22 via conserved anchor residues in a MHC peptide-like fashion.

Project description:The molecular mechanisms by which ?? T cells recognize ligand remain a mystery. The non-classical MHC molecule T22 represents the best characterized ligand for murine ?? T cells, with a motif (W … EGYEL) present in the ?? T cell receptor complementary-determining region 3? (CDR3?) loop mediating ?? T cell recognition of this molecule. Produced through V(D)J recombination, this loop is quite diverse, with different numbers and chemical types of amino acids between Trp and EGYEL, which have unknown functional consequences for T22 recognition. We have investigated the biophysical and structural effects of CDR3? loop diversity, revealing a range of affinities for T22 but a common thermodynamic pattern. Mutagenesis of these CDR3? loops defines the key anchor residues involved in T22 recognition as W … EGYEL, similar to those found for the G8 CDR3? loop, and demonstrates that spacer residues modulate but are not required for T22 recognition. Comparison of the location of these residues in the T22 interface reveals a striking similarity to peptide anchor residues in classically presented MHC peptides, with the key Trp residue of the CDR3? motif completing the deficient peptide-binding groove of T22. This suggests that ?? T cell recognition of T22 utilizes the conserved ligand-presenting nature of the MHC fold.

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Clonogenic hepatoblasts, common precursors for hepatocytic and biliary lineages, are lacking classical major histocompatibility complex class I antigen.

Project description:An in vitro colony-forming assay and flow cytometry were used to identify rat hepatoblasts as being classical MHC class I, RT1A(l-), OX18(low) intercellular adhesion molecule 1 (ICAM-1)(+). Inducible differentiation toward biliary lineage was observed in most colonies derived from single RT1A(l-) progenitors, proving their bipotentiality. These findings demonstrate the antigenic profile of clonogenic hepatoblasts and proof of their bipotency. Furthermore, whereas colony formation of adult hepatocytes required epidermal growth factor, clonal growth of hepatoblasts was potentiated without epidermal growth factor. The adult hepatic colonies consisted of RT1A(l+)OX18(+)ICAM-1(++) cells. These results indicate that hepatoblasts possess unique characteristics as compared with adult hepatocytes harboring significant proliferative activity. The phenotypic identity of hepatoblasts and the clonal culture system have relevance for identifying hepatic stem cells from adults, for studying liver development, and for cell therapy based on hepatic progenitors.

| S-EPMC17306 | biostudies-literature

Molecular determinants of peptide binding to two common rhesus macaque major histocompatibility complex class II molecules.

Project description:Major histocompatibility complex class II molecules encoded by two common rhesus macaque alleles Mamu-DRB1*0406 and Mamu-DRB*w201 have been purified, and quantitative binding assays have been established. The structural requirements for peptide binding to each molecule were characterized by testing panels of single-substitution analogs of the two previously defined epitopes HIV Env242 (Mamu-DRB1*0406 restricted) and HIV Env482 (Mamu-DRB*w201 restricted). Anchor positions of both macaque DR molecules were spaced following a position 1 (P1), P4, P6, P7, and P9 pattern. The specific binding motif associated with each molecule was distinct, but largely overlapping, and was based on crucial roles of aromatic and/or hydrophobic residues at P1, P6, and P9. Based on these results, a tentative Mamu class II DR supermotif was defined. This pattern is remarkably similar to a previously defined human HLA-DR supermotif. Similarities in binding motifs between human HLA and macaque Mamu-DR molecules were further illustrated by testing a panel of more than 60 different single-substitution analogs of the HLA-DR-restricted HA 307-319 epitope for binding to Mamu-DRB*w201 and HLA-DRB1*0101. The Mamu-DRB1*0406 and -DRB*w201 binding capacity of a set of 311 overlapping peptides spanning the entire simian immunodeficiency virus (SIV) genome was also evaluated. Ten peptides capable of binding both molecules were identified, together with 19 DRB1*0406 and 43 DRB*w201 selective binders. The Mamu-DR supermotif was found to be present in about 75% of the good binders and in 50% of peptides binding with intermediate affinity but only in approximately 25% of the peptides which did not bind either Mamu class II molecule. Finally, using flow cytometric detection of antigen-induced intracellular gamma interferon, we identify a new CD4(+) T-lymphocyte epitope encoded within the Rev protein of SIV.

| S-EPMC114676 | biostudies-literature

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