Medical Biology - Research Publications

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Author: Bouillet, Philippe × Author: Godfrey, Dale × Type: Journal Article ×

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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.
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    BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes
    Bouillet, P ; Purton, JF ; Godfrey, DI ; Zhang, LC ; Coultas, L ; Puthalakath, H ; Pellegrini, M ; Cory, S ; Adams, JM ; Strasser, A (NATURE PUBLISHING GROUP, 2002-02-21)
    During lymphocyte development, the assembly of genes coding for antigen receptors occurs by the combinatorial linking of gene segments. The stochastic nature of this process gives rise to lymphocytes that can recognize self-antigens, thereby having the potential to induce autoimmune disease. Such autoreactive lymphocytes can be silenced by developmental arrest or unresponsiveness (anergy), or can be deleted from the repertoire by cell death. In the thymus, developing T lymphocytes (thymocytes) bearing a T-cell receptor (TCR)-CD3 complex that engages self-antigens are induced to undergo programmed cell death (apoptosis), but the mechanisms ensuring this 'negative selection' are unclear. We now report that thymocytes lacking the pro-apoptotic Bcl-2 family member Bim (also known as Bcl2l11) are refractory to apoptosis induced by TCR-CD3 stimulation. Moreover, in transgenic mice expressing autoreactive TCRs that provoke widespread deletion, Bim deficiency severely impaired thymocyte killing. TCR ligation upregulated Bim expression and promoted interaction of Bim with Bcl-XL, inhibiting its survival function. These findings identify Bim as an essential initiator of apoptosis in thymocyte-negative selection.