Exceptionally high conservation of the MHC class I-related gene, MR1, among mammals.
ABSTRACT The major histocompatibility complex (MHC) class I-related gene, MR1, is a non-classical MHC class IA gene and is encoded outside the MHC region. The MR1 is responsible for activation of mucosal-associated invariant T (MAIT) cells expressing semi-invariant T cell receptors in the presence of bacteria, but its ligand has not been identified. A unique characteristic of MR1 is its high evolutionary conservation of the α1 and α2 domains corresponding to the peptide-binding domains of classical MHC class I molecules, showing about 90 % amino acid identity between human and mouse. To clarify the evolutionary history of MR1 and identify more critically conserved residues for the function of MR1, we searched for the MR1 gene using jawed vertebrate genome databases and isolated the MR1 cDNA sequences of marsupials (opossum and wallaby). A comparative genomic analysis indicated that MR1 is only present in placental and marsupial mammals and that the gene organization around MR1 is well conserved among analyzed jawed vertebrates. Moreover, the α1 and α2 domains, especially in amino acid residues presumably shaping a ligand-binding groove, were also highly conserved between placental and marsupial MR1. These findings suggest that the MR1 gene might have been established at its present location in a common ancestor of placental and marsupial mammals and that the shape of the putative ligand-binding groove in MR1 has been maintained, probably for presenting highly conserved component(s) of microbes to MAIT cells.
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ABSTRACT: The Drosophila kep1 gene encodes an RNA binding protein related to the murine QUAKING apoptotic inducer. We have previously shown that kep1 can induce apoptosis when transfected into different cell lines. To better define the role of Kep1 in apoptosis, we generated kep1 null flies. These flies were viable, but females displayed reduced fertility, with approximately half of the eggs laid from kep1- homozygotes failing to hatch. In addition, loss of kep1 suppressed GMR-rpr-mediated apoptosis in the Drosophila eye, and kep1 mutant flies had increased susceptibility to Escherichia coli infection. We found that Kep1 bound dredd RNA in vitro, and that extracts prepared from kep1 mutant ovaries had markedly reduced proteolytic cleavage activity toward the caspase-8 target substrate IETD-7-amino-4-trifluoromethyl coumarin. We observed increased levels of the beta isoform of dredd mRNA in kep1 mutants as compared with wild-type. Taken together, our results suggest that Kep1 regulates apoptosis by influencing the processing of dredd RNA.Proceedings of the National Academy of Sciences 03/2003; 100(4):1814-9. DOI:10.1073/pnas.0236048100 · 9.81 Impact Factor
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ABSTRACT: Mucosa-associated Invariant T (MAIT) cells are an evolutionarily conserved innate-like T cell subset that recognizes antigens presented by MR1 molecules. These antigens include vitamin B derivatives shared by many potentially pathogenic microbes, including Mycobacterium tuberculosis and Candida albicans. It was recently discovered that MAIT cells decay numerically and functionally in HIV-1 infection, and that they fail to recover despite several years of effective suppression of viral replication by antiretroviral therapy (ART). Here, we briefly discuss the roles of MAIT cells and their loss in HIV immunopathogenesis. We furthermore propose that the persistence of MAIT cell loss on ART needs to be taken into account when assessing the immunological response to treatment, and when treatment should commence. The importance of this T cell subset in HIV-1 infection needs further study, and interventions to restore the MAIT cell compartment should be considered. (C) 2013 Lippincott Williams & Wilkins, Inc.AIDS 04/2013; DOI:10.1097/QAD.0b013e3283620726 · 6.56 Impact Factor
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ABSTRACT: Mucosa-associated invariant T (MAIT) cells are "innate" T cells that express an invariant T-cell receptor α-chain restricted by the nonclassical MHC class I molecule MHC-related protein 1 (MR1). A recent discovery that MR1 presents vitamin B metabolites, presumably from pathogenic and/or commensal bacteria, distinguishes MAIT cells from peptide- or lipid-recognizing αβ T cells in the immune system. MAIT cells are activated by a wide variety of bacterial strains in vitro, but their role in defense against infectious assaults in vivo remains largely unknown. To investigate how MAIT cells contribute to mucosal immunity in vivo, we used a murine model of pulmonary infection by using the live vaccine strain (LVS) of Francisella tularensis. In the early acute phase of infection, MAIT cells expanded robustly in the lungs, where they preferentially accumulated after reaching their peak expansion in the late phase of infection. Throughout the course of infection, MAIT cells produced the critical cytokines IFN-γ, TNF-α, and IL-17A. Mechanistic studies showed that MAIT cells required both MR1 and IL-12 40 kDa subunit (IL-12p40) signals from infected antigen presenting cells to control F. tularensis LVS intracellular growth. Importantly, pulmonary F. tularensis LVS infection of MR1-deficient (MR1(-/-)) mice, which lack MAIT cells, revealed defects in early mucosal cytokine production, timely recruitment of IFN-γ-producing CD4(+) and CD8(+) T cells to the infected lungs, and control of pulmonary F. tularensis LVS growth. This study provides in vivo evidence demonstrating that MAIT cells are an important T-cell subset with activities that influence the innate and adaptive phases of mucosal immunity.Proceedings of the National Academy of Sciences 07/2013; DOI:10.1073/pnas.1302799110 · 9.81 Impact Factor