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Caspase-8 inactivation in T cells increases necroptosis and suppresses autoimmunity in Bim-/- mice.

Bohgaki T, Mozo J, Salmena L, Matysiak-Zablocki E, Bohgaki M, Sanchez O, Strasser A, Hakem A, Hakem R - J. Cell Biol. (2011)

Bottom Line: Dysregulation of either the extrinsic or intrinsic apoptotic pathway can lead to various diseases including immune disorders and cancer.In addition to its role in the extrinsic apoptotic pathway, caspase-8 plays nonapoptotic functions and is essential for T cell homeostasis.We show that, similar to caspase-8(-/-) T cells, Bim(-/-) T cells that also lack caspase-8 displayed elevated levels of necroptosis and that inhibition of this cell death process fully rescued the survival and proliferation of these cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.

ABSTRACT
Dysregulation of either the extrinsic or intrinsic apoptotic pathway can lead to various diseases including immune disorders and cancer. In addition to its role in the extrinsic apoptotic pathway, caspase-8 plays nonapoptotic functions and is essential for T cell homeostasis. The pro-apoptotic BH3-only Bcl-2 family member Bim is important for the intrinsic apoptotic pathway and its inactivation leads to autoimmunity that is further exacerbated by loss of function of the death receptor Fas. We report that inactivation of caspase-8 in T cells of Bim(-/-) mice restrained their autoimmunity and extended their life span. We show that, similar to caspase-8(-/-) T cells, Bim(-/-) T cells that also lack caspase-8 displayed elevated levels of necroptosis and that inhibition of this cell death process fully rescued the survival and proliferation of these cells. Collectively, our data demonstrate that inactivation of caspase-8 suppresses the survival and proliferative capacity of Bim(-/-) T cells and restrains autoimmunity in Bim(-/-) mice.

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Combined loss of caspase-8 and Bim causes additive but not synergistic resistance to apoptotic stimuli. Apoptotic responses of thymocytes (A–E) and activated T cells (F–J) lacking caspase-8, Bim, or both are shown. Thymocytes or activated T cells from tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT littermates were challenged in culture with anti-Fas antibody (A and F), anti-CD3 antibody (B and G), dexamethasone (C and H), or ionizing radiation (D and I), and the extent of cell survival was assessed 24 h later. (E and J) Thymocyte and activated T cell survival in simple medium (termed death by neglect or growth factor deprivation–induced death) were also examined. Data represent the mean ± SEM (error bars) of 3–5 young mice for each genotype. Asterisks indicate significant differences compared with WT thymocytes or activated T cells (P < 0.05).
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fig2: Combined loss of caspase-8 and Bim causes additive but not synergistic resistance to apoptotic stimuli. Apoptotic responses of thymocytes (A–E) and activated T cells (F–J) lacking caspase-8, Bim, or both are shown. Thymocytes or activated T cells from tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT littermates were challenged in culture with anti-Fas antibody (A and F), anti-CD3 antibody (B and G), dexamethasone (C and H), or ionizing radiation (D and I), and the extent of cell survival was assessed 24 h later. (E and J) Thymocyte and activated T cell survival in simple medium (termed death by neglect or growth factor deprivation–induced death) were also examined. Data represent the mean ± SEM (error bars) of 3–5 young mice for each genotype. Asterisks indicate significant differences compared with WT thymocytes or activated T cells (P < 0.05).

Mentions: To investigate the effects of combined inactivation of caspase-8 and Bim on apoptosis, we examined the responses of tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT thymocytes as well as activated peripheral T cells to a range of cytotoxic stimuli that trigger either the extrinsic or intrinsic apoptotic pathway. Previous studies demonstrated the resistance of tcasp8−/− thymocytes and activated T cells to Fas-mediated killing, whereas Bim−/− thymocytes and activated T cells remain normally sensitive to this apoptotic stimulus (Bouillet et al., 1999; Salmena et al., 2003). Examination of apoptosis demonstrated that tcasp8−/− and tcasp8−/−Bim−/− thymocytes and activated T cells were highly resistant to Fas-mediated killing (Figs. 2, A and F). The effects of combined inactivation of caspase-8 and Bim on thymocyte and activated T cell apoptosis in response to growth factor withdrawal, DNA damage, or treatment with dexamethasone were also assessed, as resistance to these apoptotic stimuli has been associated with loss of Bim (Bouillet et al., 1999) but not with loss of caspase-8 (Salmena et al., 2003). Bim is also critical for the deletion of autoreactive thymocytes and TCR/CD3 cross-linking–induced thymocyte apoptosis (Bouillet et al., 2002). Contrasting with tcasp8−/− thymocytes, tcasp8−/−Bim−/− thymocytes exhibited similar resistance as Bim−/− thymocytes to anti-CD3 antibody treatment, dexamethasone, and ionizing radiation as well as growth factor deprivation (Fig. 2, B–E and G–J).


Caspase-8 inactivation in T cells increases necroptosis and suppresses autoimmunity in Bim-/- mice.

Bohgaki T, Mozo J, Salmena L, Matysiak-Zablocki E, Bohgaki M, Sanchez O, Strasser A, Hakem A, Hakem R - J. Cell Biol. (2011)

Combined loss of caspase-8 and Bim causes additive but not synergistic resistance to apoptotic stimuli. Apoptotic responses of thymocytes (A–E) and activated T cells (F–J) lacking caspase-8, Bim, or both are shown. Thymocytes or activated T cells from tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT littermates were challenged in culture with anti-Fas antibody (A and F), anti-CD3 antibody (B and G), dexamethasone (C and H), or ionizing radiation (D and I), and the extent of cell survival was assessed 24 h later. (E and J) Thymocyte and activated T cell survival in simple medium (termed death by neglect or growth factor deprivation–induced death) were also examined. Data represent the mean ± SEM (error bars) of 3–5 young mice for each genotype. Asterisks indicate significant differences compared with WT thymocytes or activated T cells (P < 0.05).
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3198166&req=5

fig2: Combined loss of caspase-8 and Bim causes additive but not synergistic resistance to apoptotic stimuli. Apoptotic responses of thymocytes (A–E) and activated T cells (F–J) lacking caspase-8, Bim, or both are shown. Thymocytes or activated T cells from tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT littermates were challenged in culture with anti-Fas antibody (A and F), anti-CD3 antibody (B and G), dexamethasone (C and H), or ionizing radiation (D and I), and the extent of cell survival was assessed 24 h later. (E and J) Thymocyte and activated T cell survival in simple medium (termed death by neglect or growth factor deprivation–induced death) were also examined. Data represent the mean ± SEM (error bars) of 3–5 young mice for each genotype. Asterisks indicate significant differences compared with WT thymocytes or activated T cells (P < 0.05).
Mentions: To investigate the effects of combined inactivation of caspase-8 and Bim on apoptosis, we examined the responses of tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT thymocytes as well as activated peripheral T cells to a range of cytotoxic stimuli that trigger either the extrinsic or intrinsic apoptotic pathway. Previous studies demonstrated the resistance of tcasp8−/− thymocytes and activated T cells to Fas-mediated killing, whereas Bim−/− thymocytes and activated T cells remain normally sensitive to this apoptotic stimulus (Bouillet et al., 1999; Salmena et al., 2003). Examination of apoptosis demonstrated that tcasp8−/− and tcasp8−/−Bim−/− thymocytes and activated T cells were highly resistant to Fas-mediated killing (Figs. 2, A and F). The effects of combined inactivation of caspase-8 and Bim on thymocyte and activated T cell apoptosis in response to growth factor withdrawal, DNA damage, or treatment with dexamethasone were also assessed, as resistance to these apoptotic stimuli has been associated with loss of Bim (Bouillet et al., 1999) but not with loss of caspase-8 (Salmena et al., 2003). Bim is also critical for the deletion of autoreactive thymocytes and TCR/CD3 cross-linking–induced thymocyte apoptosis (Bouillet et al., 2002). Contrasting with tcasp8−/− thymocytes, tcasp8−/−Bim−/− thymocytes exhibited similar resistance as Bim−/− thymocytes to anti-CD3 antibody treatment, dexamethasone, and ionizing radiation as well as growth factor deprivation (Fig. 2, B–E and G–J).

Bottom Line: Dysregulation of either the extrinsic or intrinsic apoptotic pathway can lead to various diseases including immune disorders and cancer.In addition to its role in the extrinsic apoptotic pathway, caspase-8 plays nonapoptotic functions and is essential for T cell homeostasis.We show that, similar to caspase-8(-/-) T cells, Bim(-/-) T cells that also lack caspase-8 displayed elevated levels of necroptosis and that inhibition of this cell death process fully rescued the survival and proliferation of these cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.

ABSTRACT
Dysregulation of either the extrinsic or intrinsic apoptotic pathway can lead to various diseases including immune disorders and cancer. In addition to its role in the extrinsic apoptotic pathway, caspase-8 plays nonapoptotic functions and is essential for T cell homeostasis. The pro-apoptotic BH3-only Bcl-2 family member Bim is important for the intrinsic apoptotic pathway and its inactivation leads to autoimmunity that is further exacerbated by loss of function of the death receptor Fas. We report that inactivation of caspase-8 in T cells of Bim(-/-) mice restrained their autoimmunity and extended their life span. We show that, similar to caspase-8(-/-) T cells, Bim(-/-) T cells that also lack caspase-8 displayed elevated levels of necroptosis and that inhibition of this cell death process fully rescued the survival and proliferation of these cells. Collectively, our data demonstrate that inactivation of caspase-8 suppresses the survival and proliferative capacity of Bim(-/-) T cells and restrains autoimmunity in Bim(-/-) mice.

Show MeSH
Related in: MedlinePlus