Medical Biology - Research Publications

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Author: Godfrey, Dale × Author: Strasser, Andreas × End date: 2018 × Start date: 2016 × Type: Journal Article ×

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    PTPN2 regulates T cell lineage commitment and αβ versus γδ specification
    Wiede, F ; Dudakov, JA ; Lu, K-H ; Dodd, GT ; Butt, T ; Godfrey, DI ; Strasser, A ; Boyd, RL ; Tiganis, T (ROCKEFELLER UNIV PRESS, 2017-09)
    In the thymus, hematopoietic progenitors commit to the T cell lineage and undergo sequential differentiation to generate diverse T cell subsets, including major histocompatibility complex (MHC)-restricted αβ T cell receptor (TCR) T cells and non-MHC-restricted γδ TCR T cells. The factors controlling precursor commitment and their subsequent maturation and specification into αβ TCR versus γδ TCR T cells remain unclear. Here, we show that the tyrosine phosphatase PTPN2 attenuates STAT5 (signal transducer and activator of transcription 5) signaling to regulate T cell lineage commitment and SRC family kinase LCK and STAT5 signaling to regulate αβ TCR versus γδ TCR T cell development. Our findings identify PTPN2 as an important regulator of critical checkpoints that dictate the commitment of multipotent precursors to the T cell lineage and their subsequent maturation into αβ TCR or γδ TCR T 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.