Anatomy and Neuroscience - Research Publications

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Author: Eckle, Sidonia × End date: 2019 × Start date: 2000 ×

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    Antigen-loaded MR1 tetramers define T cell receptor heterogeneity in mucosal-associated invariant T cells
    Reantragoon, R ; Corbett, AJ ; Sakala, IG ; Gherardin, NA ; Furness, JB ; Chen, Z ; Eckle, SBG ; Uldrich, AP ; Birkinshaw, RW ; Patel, O ; Kostenko, L ; Meehan, B ; Kedzierska, K ; Liu, L ; Fairlie, DP ; Hansen, TH ; Godfrey, DI ; Rossjohn, J ; McCluskey, J ; Kjer-Nielsen, L (ROCKEFELLER UNIV PRESS, 2013-10-21)
    Mucosal-associated invariant T cells (MAIT cells) express a semi-invariant T cell receptor (TCR) α-chain, TRAV1-2-TRAJ33, and are activated by vitamin B metabolites bound by the major histocompatibility complex (MHC)-related class I-like molecule, MR1. Understanding MAIT cell biology has been restrained by the lack of reagents to specifically identify and characterize these cells. Furthermore, the use of surrogate markers may misrepresent the MAIT cell population. We show that modified human MR1 tetramers loaded with the potent MAIT cell ligand, reduced 6-hydroxymethyl-8-D-ribityllumazine (rRL-6-CH₂OH), specifically detect all human MAIT cells. Tetramer(+) MAIT subsets were predominantly CD8(+) or CD4(-)CD8(-), although a small subset of CD4(+) MAIT cells was also detected. Notably, most human CD8(+) MAIT cells were CD8α(+)CD8β(-/lo), implying predominant expression of CD8αα homodimers. Tetramer-sorted MAIT cells displayed a T(H)1 cytokine phenotype upon antigen-specific activation. Similarly, mouse MR1-rRL-6-CH₂OH tetramers detected CD4(+), CD4(-)CD8(-) and CD8(+) MAIT cells in Vα19 transgenic mice. Both human and mouse MAIT cells expressed a broad TCR-β repertoire, and although the majority of human MAIT cells expressed TRAV1-2-TRAJ33, some expressed TRAJ12 or TRAJ20 genes in conjunction with TRAV1-2. Accordingly, MR1 tetramers allow precise phenotypic characterization of human and mouse MAIT cells and revealed unanticipated TCR heterogeneity in this population.
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    MAIT cells protect against pulmonary Legionella longbeachae infection
    Wang, H ; D'Souza, C ; Lim, XY ; Kostenko, L ; Pediongco, TJ ; Eckle, SBG ; Meehan, BS ; Shi, M ; Wang, N ; Li, S ; Liu, L ; Mak, JYW ; Fairlie, DP ; Iwakura, Y ; Gunnersen, JM ; Stent, AW ; Godfrey, DI ; Rossjohn, J ; Westall, GP ; Kjer-Nielsen, L ; Strugnell, RA ; McCluskey, J ; Corbett, AJ ; Hinks, TSC ; Chen, Z (NATURE RESEARCH, 2018-08-22)
    Mucosal associated invariant T (MAIT) cells recognise conserved microbial metabolites from riboflavin synthesis. Striking evolutionary conservation and pulmonary abundance implicate them in antibacterial host defence, yet their functions in protection against clinically important pathogens are unknown. Here we show that mouse Legionella longbeachae infection induces MR1-dependent MAIT cell activation and rapid pulmonary accumulation of MAIT cells associated with immune protection detectable in immunocompetent host animals. MAIT cell protection is more evident in mice lacking CD4+ cells, and adoptive transfer of MAIT cells rescues immunodeficient Rag2-/-γC-/- mice from lethal Legionella infection. Protection is dependent on MR1, IFN-γ and GM-CSF, but not IL-17A, TNF or perforin, and enhanced protection is detected earlier after infection of mice antigen-primed to boost MAIT cell numbers before infection. Our findings define a function for MAIT cells in protection against a major human pathogen and indicate a potential role for vaccination to enhance MAIT cell immunity.
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    Antigen-loaded MR1 tetramers define T cell receptor heterogeneity in mucosal-associated invariant T cells
    Reantragoon, Rangsima ; Corbett, Alexandra J. ; Sakala, Isaac G. ; Gherardin, Nicholas A. ; Furness, John B. ; CHEN, ZHENJUN ; Eckle, Sidonia B.G. ; Uldrich, Adam P. ; Birkinshaw, Richard W. ; Patel, Onisha ; KOSTENKO, LYUDMILA ; MEEHAN, BRONWYN ; KEDZIERSKA, KATHERINE ; Liu, Ligong ; Fairlie, David P. ; Hansen, Ted H. ; GODFREY, DALE I. ; ROSSJOHN, JAMIE ; MCCLUSKEY, JAMES ; KJER-NIELSEN, LARS (Rockefeller University Press, 2013)
    Mucosal-associated invariant T cells (MAIT cells) express a semi-invariant T cell receptor (TCR) alpha-chain, TRAV1-2-TRAJ33, and are activated by vitamin B metabolites bound by the major histocompatibility complex (MHC)-related class I-like molecule, MR1. Understanding MAIT cell biology has been restrained by the lack of reagents to specifically identify and characterize these cells. Furthermore, the use of surrogate markers may misrepresent the MAIT cell population. We show that modified human MR1 tetramers loaded with the potent MAIT cell ligand, reduced 6-hydroxymethyl-8-D-ribityllumazine (rRL-6-CH2OH), specifically detect all human MAIT cells. Tetramer(+) MAIT subsets were predominantly CD8(+) or CD4(-)CD8(-), although a small subset of CD4(+) MAIT cells was also detected. Notably, most human CD8(+) MAIT cells were CD8 alpha(+)CD8 beta(-/lo), implying predominant expression of CD8 alpha alpha homodimers. Tetramer-sorted MAIT cells displayed a T(H)1 cytokine phenotype upon antigen-specific activation. Similarly, mouse MR1-rRL-6-CH2OH tetramers detected CD4(+), CD4(-)CD8(-) and CD8(+) MAIT cells in V. 19 transgenic mice. Both human and mouse MAIT cells expressed a broad TCR-beta repertoire, and although the majority of human MAIT cells expressed TRAV1-2-TRAJ33, some expressed TRAJ12 or TRAJ20 genes in conjunction with TRAV1-2. Accordingly, MR1 tetramers allow precise phenotypic characterization of human and mouse MAIT cells and revealed unanticipated TCR heterogeneity in this population.