Medical Biology - Research Publications

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Author: Koay, Hui Fern × Start date: 2016 × End date: 2016 × Type: Journal Article ×

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    A three-stage intrathymic development pathway for the mucosal-associated invariant T cell lineage
    Koay, H-F ; Gherardin, NA ; Enders, A ; Loh, L ; Mackay, LK ; Almeida, CF ; Russ, BE ; Nold-Petry, CA ; Nold, MF ; Bedoui, S ; Chen, Z ; Corbett, AJ ; Eckle, SBG ; Meehan, B ; d'Udekem, Y ; Konstantinov, IE ; Lappas, M ; Liu, L ; Goodnow, CC ; Fairlie, DP ; Rossjohn, J ; Chong, MM ; Kedzierska, K ; Berzins, SP ; Belz, GT ; McCluskey, J ; Uldrich, AP ; Godfrey, DI ; Pellicci, DG (NATURE PUBLISHING GROUP, 2016-11)
    Mucosal-associated invariant T cells (MAIT cells) detect microbial vitamin B2 derivatives presented by the antigen-presenting molecule MR1. Here we defined three developmental stages and checkpoints for the MAIT cell lineage in humans and mice. Stage 1 and stage 2 MAIT cells predominated in thymus, while stage 3 cells progressively increased in abundance extrathymically. Transition through each checkpoint was regulated by MR1, whereas the final checkpoint that generated mature functional MAIT cells was controlled by multiple factors, including the transcription factor PLZF and microbial colonization. Furthermore, stage 3 MAIT cell populations were expanded in mice deficient in the antigen-presenting molecule CD1d, suggestive of a niche shared by MAIT cells and natural killer T cells (NKT cells). Accordingly, this study maps the developmental pathway and checkpoints that control the generation of functional MAIT cells.
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    Linear ubiquitin chain assembly complex coordinates late thymic T-cell differentiation and regulatory T-cell homeostasis
    Teh, CE ; Lalaoui, N ; Jain, R ; Policheni, AN ; Heinlein, M ; Alvarez-Diaz, S ; Sheridan, JM ; Rieser, E ; Deuser, S ; Darding, M ; Koay, H-F ; Hu, Y ; Kupresanin, F ; O'Reilly, LA ; Godfrey, DI ; Smyth, GK ; Bouillet, P ; Strasser, A ; Walczak, H ; Silke, J ; Gray, DHD (NATURE PUBLISHING GROUP, 2016-11-18)
    The linear ubiquitin chain assembly complex (LUBAC) is essential for innate immunity in mice and humans, yet its role in adaptive immunity is unclear. Here we show that the LUBAC components HOIP, HOIL-1 and SHARPIN have essential roles in late thymocyte differentiation, FOXP3+ regulatory T (Treg)-cell development and Treg cell homeostasis. LUBAC activity is not required to prevent TNF-induced apoptosis or necroptosis but is necessary for the transcriptional programme of the penultimate stage of thymocyte differentiation. Treg cell-specific ablation of HOIP causes severe Treg cell deficiency and lethal immune pathology, revealing an ongoing requirement of LUBAC activity for Treg cell homeostasis. These data reveal stage-specific requirements for LUBAC in coordinating the signals required for T-cell differentiation.