Microbiology & Immunology - Research Publications

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    A conserved human T cell population targets mycobacterial antigens presented by CD1b
    Van Rhijn, I ; Kasmar, A ; de Jong, A ; Gras, S ; Bhati, M ; Doorenspleet, ME ; de Vries, N ; Godfrey, DI ; Altman, JD ; de Jager, W ; Rossjohn, J ; Moody, DB (NATURE PUBLISHING GROUP, 2013-07)
    Human T cell antigen receptors (TCRs) pair in millions of combinations to create complex and unique T cell repertoires for each person. Through the use of tetramers to analyze TCRs reactive to the antigen-presenting molecule CD1b, we detected T cells with highly stereotyped TCR α-chains present among genetically unrelated patients with tuberculosis. The germline-encoded, mycolyl lipid-reactive (GEM) TCRs had an α-chain bearing the variable (V) region TRAV1-2 rearranged to the joining (J) region TRAJ9 with few nontemplated (N)-region additions. Analysis of TCRs by high-throughput sequencing, binding and crystallography showed linkage of TCRα sequence motifs to high-affinity recognition of antigen. Thus, the CD1-reactive TCR repertoire is composed of at least two compartments: high-affinity GEM TCRs, and more-diverse TCRs with low affinity for CD1b-lipid complexes. We found high interdonor conservation of TCRs that probably resulted from selection by a nonpolymorphic antigen-presenting molecule and an immunodominant antigen.
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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.