Medical Biology - Research Publications

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Author: Gray, Daniel × Author: Strasser, Andreas × End date: 2018 × Type: Journal Article ×

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    Cell death and thymic tolerance
    Daley, SR ; Teh, C ; Hu, DY ; Strasser, A ; Gray, DHD (WILEY, 2017-05)
    The differentiation of hematopoietic precursors into the many functionally distinct T-cell types produced by the thymus is a complex process. It proceeds through a series of stages orchestrated by a variety of thymic microenvironments that shape the T-cell developmental processes. Numerous cytokine and cell surface receptors direct thymocyte differentiation but the primary determinant of cell fate is the engagement of the T-cell antigen receptor (TCR). The strength of the TCR signal and the maturation stage of the thymocyte receiving it can direct the various differentiation programs or, alternatively, end the process by inducing cell death. The regulation of thymocyte death is critical for the efficiency of thymic T-cell differentiation and the preservation of immune tolerance. A detailed knowledge of mechanisms that eliminate thymocytes from the T-cell repertoire is essential to understand the "logic" of T-cell selection in the thymus. This review focuses on the central role of the BCL-2 family of proteins in the apoptotic checkpoints that punctuate thymocyte differentiation and the consequences of defects in these processes.
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    Cell cycle progression dictates the requirement for BCL2 in natural killer cell survival
    Viant, C ; Guia, S ; Hennessy, RJ ; Rautela, J ; Pham, K ; Bernat, C ; Goh, W ; Jiao, Y ; Delconte, R ; Roger, M ; Simon, V ; Souza-Fonseca-Guimaraes, F ; Grabow, S ; Belz, GT ; Kile, BT ; Strasser, A ; Gray, D ; Hodgkin, PD ; Beutler, B ; Vivier, E ; Ugolini, S ; Huntington, ND (ROCKEFELLER UNIV PRESS, 2017-02)
    Natural killer (NK) cells are innate lymphoid cells with antitumor functions. Using an N-ethyl-N-nitrosourea (ENU)-induced mutagenesis screen in mice, we identified a strain with an NK cell deficiency caused by a hypomorphic mutation in the Bcl2 (B cell lymphoma 2) gene. Analysis of these mice and the conditional deletion of Bcl2 in NK cells revealed a nonredundant intrinsic requirement for BCL2 in NK cell survival. In these mice, NK cells in cycle were protected against apoptosis, and NK cell counts were restored in inflammatory conditions, suggesting a redundant role for BCL2 in proliferating NK cells. Consistent with this, cycling NK cells expressed higher MCL1 (myeloid cell leukemia 1) levels in both control and BCL2-null mice. Finally, we showed that deletion of BIM restored survival in BCL2-deficient but not MCL1-deficient NK cells. Overall, these data demonstrate an essential role for the binding of BCL2 to BIM in the survival of noncycling NK cells. They also favor a model in which MCL1 is the dominant survival protein in proliferating NK 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.