Bad Can Act as a Key Regulator of  T Cell Apoptosis and T Cell Development

Mok, Chen-Lang; Gil‐Gómez, Gabriel; Williams, Owen; Coles, Mark; Taga, Samir; Tolaini, Mauro; Norton, Trisha; Kioussis, Dimitris; Brady, Hugh J.M.

doi:10.1084/jem.189.3.575

Cited by 96 publications

(90 citation statements)

References 52 publications

(107 reference statements)

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“…However, a previous array study to find GRregulated genes in phytohaemaglutinin-stimulated peripheral blood mononuclear cells showed upregulation of STAT1 and BAD in agreement with our results (Galon et al, 2002). Although no direct regulation of BAD by GR has been shown previously, Gc-induced apoptosis in primary T cells in vivo and in vitro is associated with a significant upregulation of BAD (Mok et al, 1999).…”

Section: Discussionsupporting

confidence: 92%

Glucocorticoid receptor overexpression exerts an antisurvival effect on human small cell lung cancer cells

et al. 2007

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Section: Discussionsupporting

confidence: 92%

Glucocorticoid receptor overexpression exerts an antisurvival effect on human small cell lung cancer cells

et al. 2007

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“…Previous studies of cell lines have shown that IL-7 can promote cell survival by inactivating Bad through its Akt/PKBdependent phosphorylation [31]. However, detailed analysis of F5 transgenic mice that over-express Bad, consequently inducing thymocyte apoptosis [32] (Supporting Information Fig. 4A), revealed no evidence of defects in naïve T-cell survival in vitro (Supporting Information Fig.…”

Section: Il-7 Signalling In Vivo Regulates Mitochondrial Homeostasismentioning

confidence: 95%

“…(F5Rag1 À/À Â C57BL/6J Ly5.1)F1 mice were used as controls throughout. These strains and F5 Rag1 À/À Bad huCD2 [32], Rag1 À/À , Il7r À/À and F5 Rag1 À/À mice were bred in a conventional colony free of pathogens at the NIMR, London. …”

mentioning

confidence: 99%

IL‐7 determines the homeostatic fitness of T cells by distinct mechanisms at different signalling thresholds in vivo

Pearson¹,

Silva²,

Saini³

et al. 2011

Eur J Immunol

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The cytokine interleukin (IL)-7 is essential for Treg-cell homeostasis. It remains unclear, however, whether IL-7 regulates the homeostatic fitness of T cells quantitatively and, if so, by what mechanisms. We addressed this question by analysing T cells exposed to different levels of IL-7 signalling in vivo. Using TCR transgenic mice that conditionally express IL-7Ra, we show that T-cell longevity in the absence of survival cues is not a cellintrinsic property but rather a dynamic process of which IL-7 signalling is a key regulator. Naïve T cells deficient in IL-7Ra expression underwent rapid cell death within hours of in vitro culture. In contrast, the same T cells from lymphopenic hosts, in which IL-7 is nonlimiting, were able to survive in culture independently of growth factors for many days. Surprisingly, different levels of IL-7 signalling in vivo evoked distinct molecular mechanisms to regulate homeostatic fitness. When IL-7 was non-limiting, increased survival was associated with up-regulation of anti-apoptotic Bcl2 family members. In contrast, in T-cell replete conditions i.e. when IL-7 is limiting, we found evidence that IL-7 regulated T-cell fitness by distinct non-transcriptional mechanisms. Together, these data demonstrate a quantitative aspect to IL-7 signalling dependent on distinct molecular mechanisms.Key words: Fitness . Homeostasis . IL-7 . T cells Supporting Information available onlineIntroduction A commonly evoked concept in studies of lymphocyte homeostasis is that of cellular fitness. Whether a cell lives or dies in a particular context, such as effector cell transition to a memory state, or survival of recent thymic emigrants entering a replete peripheral compartment, is a function of its relative fitness [1]. The cytokine IL-7 plays a fundamental role in homeostasis of the peripheral T-cell compartment [2][3][4]. IL-7 is limiting in replete conditions and is a key determinant of the T-cell compartment size, since total T-cell numbers in mice lacking one or other CD4 1 and CD8 1 subsets are near-identical to those in mice with both subsets [5][6][7]. Conversely, genetic over-expression of 9] or its administration in vivo [10] increases T-cell numbers. It is likely, therefore, that IL-7 is a key determinant of homeostatic fitness. Lymphocytes are unlikely to have unfettered access to the multiple environmental cues required for their survival, but rather receive such signals on a sporadic basis. Consistent with this view, chemokines direct T cells to sites of IL-7 production within lymph nodes [11]. Thus, the homeostatic fitness of a T cell and consequently whether it lives or dies in a given homeostatic context may depend on how frequently it receives survival signals such as IL-7 and how long the cell can persist in the absence of such survival signalling.Ã These authors contributed equally to this work. 3656The mechanisms by which IL-7 maintains T-cell survival, and therefore regulate cellular fitness, have been the subject of numerous studies. Many of these have focused on the transc...

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“…In particular, overexpression of the anti-apoptotic members of this family in B and T cells delays entry into S-phase [5][6][7] and accelerates withdrawal from the cell cycle [8,9]. In contrast, overexpression of pro-apoptotic members such as Bax or Bad in T cells of transgenic mice increases the number of cycling thymocytes, favouring entry into S-phase [6,10]. The ability of Bcl-2 to interfere with cell-cycle progression is not limited to lymphoid cells, but has also been observed in murine fibroblasts [7,11].…”

Section: Introductionmentioning

confidence: 99%

Bcl-2 activates a programme of premature senescence in human carcinoma cells

Crescenzi

Palumbo

Brady

2003

Biochemical Journal

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The apoptosis regulator Bcl-2 has been shown to modulate cellcycle progression, favouring a quiescent state over a proliferative state, in both normal and tumour cells. We show here that constitutive expression of Bcl-2 in human carcinoma cells results in a cell-cycle arrest that within a few days can become irreversible. Arrested cells acquire a senescent-like phenotype, which consists of several characteristic morphological alterations and increased activity of senescence-associated β-galactosidase. The induction of the premature senescence programme is mediated by inhibition of Cdk2 kinase activity, and p27 KIP1 is required to maintain the senescent phenotype. We propose that the ability to activate an endogenous premature senescence programme allows Bcl-2 to suppress tumour growth. These results suggest that the downregulation of Bcl-2 expression, which has been observed during the development and progression of human carcinoma, is related to the ability of Bcl-2 to severely hamper the growth of carcinoma cells and to induce a permanent cell-cycle arrest, with the features of senescence.

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Bad Can Act as a Key Regulator of T Cell Apoptosis and T Cell Development

Cited by 96 publications

References 52 publications

Glucocorticoid receptor overexpression exerts an antisurvival effect on human small cell lung cancer cells

Glucocorticoid receptor overexpression exerts an antisurvival effect on human small cell lung cancer cells

IL‐7 determines the homeostatic fitness of T cells by distinct mechanisms at different signalling thresholds in vivo

Bcl-2 activates a programme of premature senescence in human carcinoma cells

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