Limits...
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.

Show MeSH

Related in: MedlinePlus

Effect of T cell specific loss of caspase-8 on splenomegaly and lymphocyte hyperplasia in Bim−/− mice. Representative spleens from tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT young (A) and old (D) mice. Total numbers of Thy1.2+B220− T cells and Thy1.2−B220+ B cells in spleens from tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT young (B) and old (E) mice. Absolute numbers of effector memory T cells (CD4+CD44+CD62L−) in spleens of tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT young (C) and old (F) mice. The values represent the mean ± SEM (error bars) of 10 mice for each genotype and age, and were compared by ANOVA testing. Young mice were 6–8 wk of age, and old mice were >6 mo of age. *, P < 0.05 compared with WT mice; •, P < 0.05 compared with tcasp8−/− mice; Δ, P < 0.05 compared with Bim−/− mice. Bars, 1 cm.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig3: Effect of T cell specific loss of caspase-8 on splenomegaly and lymphocyte hyperplasia in Bim−/− mice. Representative spleens from tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT young (A) and old (D) mice. Total numbers of Thy1.2+B220− T cells and Thy1.2−B220+ B cells in spleens from tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT young (B) and old (E) mice. Absolute numbers of effector memory T cells (CD4+CD44+CD62L−) in spleens of tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT young (C) and old (F) mice. The values represent the mean ± SEM (error bars) of 10 mice for each genotype and age, and were compared by ANOVA testing. Young mice were 6–8 wk of age, and old mice were >6 mo of age. *, P < 0.05 compared with WT mice; •, P < 0.05 compared with tcasp8−/− mice; Δ, P < 0.05 compared with Bim−/− mice. Bars, 1 cm.

Mentions: Caspase-8 and Bim are both important for maintaining peripheral T cell homeostasis (Bouillet et al., 1999; Salmena et al., 2003; Krammer et al., 2007). Examination of young mice revealed a similar extent of splenomegaly and lymphadenopathy in tcasp8−/−Bim−/− and Bim−/− mice, whereas tcasp8−/− mice had normal spleen and lymph node (LN) cellularity (Fig. 3, A and B; and Fig. S2, A and B). Splenomegaly of young tcasp8−/−Bim−/− mice was mainly associated with accumulation of B cells, whereas their lymphadenopathy was associated with an increased number of both T and B cell populations (Figs. 3 B and S2 B).


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)

Effect of T cell specific loss of caspase-8 on splenomegaly and lymphocyte hyperplasia in Bim−/− mice. Representative spleens from tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT young (A) and old (D) mice. Total numbers of Thy1.2+B220− T cells and Thy1.2−B220+ B cells in spleens from tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT young (B) and old (E) mice. Absolute numbers of effector memory T cells (CD4+CD44+CD62L−) in spleens of tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT young (C) and old (F) mice. The values represent the mean ± SEM (error bars) of 10 mice for each genotype and age, and were compared by ANOVA testing. Young mice were 6–8 wk of age, and old mice were >6 mo of age. *, P < 0.05 compared with WT mice; •, P < 0.05 compared with tcasp8−/− mice; Δ, P < 0.05 compared with Bim−/− mice. Bars, 1 cm.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig3: Effect of T cell specific loss of caspase-8 on splenomegaly and lymphocyte hyperplasia in Bim−/− mice. Representative spleens from tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT young (A) and old (D) mice. Total numbers of Thy1.2+B220− T cells and Thy1.2−B220+ B cells in spleens from tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT young (B) and old (E) mice. Absolute numbers of effector memory T cells (CD4+CD44+CD62L−) in spleens of tcasp8−/−Bim−/−, tcasp8−/−, Bim−/−, and WT young (C) and old (F) mice. The values represent the mean ± SEM (error bars) of 10 mice for each genotype and age, and were compared by ANOVA testing. Young mice were 6–8 wk of age, and old mice were >6 mo of age. *, P < 0.05 compared with WT mice; •, P < 0.05 compared with tcasp8−/− mice; Δ, P < 0.05 compared with Bim−/− mice. Bars, 1 cm.
Mentions: Caspase-8 and Bim are both important for maintaining peripheral T cell homeostasis (Bouillet et al., 1999; Salmena et al., 2003; Krammer et al., 2007). Examination of young mice revealed a similar extent of splenomegaly and lymphadenopathy in tcasp8−/−Bim−/− and Bim−/− mice, whereas tcasp8−/− mice had normal spleen and lymph node (LN) cellularity (Fig. 3, A and B; and Fig. S2, A and B). Splenomegaly of young tcasp8−/−Bim−/− mice was mainly associated with accumulation of B cells, whereas their lymphadenopathy was associated with an increased number of both T and B cell populations (Figs. 3 B and S2 B).

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