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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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T cell–specific loss of caspase-8 inhibits the development of autoimmune disease in Bim−/− mice and increases their lifespan. (A) Representative immunohistochemical staining of lungs (left) and kidneys (right) from 13-mo-old mice of the indicated genotypes using HE, anti-CD3 antibody (red), and anti-B220 antibody (brown). Kidney sections were also stained with anti-IgG antibodies to assess the deposition of immune complexes (right). Bars, 100 µm. (B) Kaplan-Meier analysis representing the percent survival versus age in days of cohorts of WT (n = 15), tcasp8−/− (n = 25), Bim−/− (n = 20), and tcasp8−/−Bim−/− (n = 20) mice. The survival of tcasp8−/−Bim−/− mice was significantly extended compared with tcasp8−/− and Bim−/− mice (P < 0.05). (C) A model for the restrained autoimmunity of tcasp8−/−Bim−/− mice compared with Bim−/− littermates. Autoreactive T cells that escape negative selection in Bim−/− mice expand and mediate autoimmunity. Caspase-8–deficient Bim−/− T cells that escape negative selection in tcasp8−/−Bim−/− mice display elevated levels of necroptosis and impaired proliferation, and these defects lead to restrained autoimmunity and prolonged survival of tcasp8−/−Bim−/− mice.
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fig7: T cell–specific loss of caspase-8 inhibits the development of autoimmune disease in Bim−/− mice and increases their lifespan. (A) Representative immunohistochemical staining of lungs (left) and kidneys (right) from 13-mo-old mice of the indicated genotypes using HE, anti-CD3 antibody (red), and anti-B220 antibody (brown). Kidney sections were also stained with anti-IgG antibodies to assess the deposition of immune complexes (right). Bars, 100 µm. (B) Kaplan-Meier analysis representing the percent survival versus age in days of cohorts of WT (n = 15), tcasp8−/− (n = 25), Bim−/− (n = 20), and tcasp8−/−Bim−/− (n = 20) mice. The survival of tcasp8−/−Bim−/− mice was significantly extended compared with tcasp8−/− and Bim−/− mice (P < 0.05). (C) A model for the restrained autoimmunity of tcasp8−/−Bim−/− mice compared with Bim−/− littermates. Autoreactive T cells that escape negative selection in Bim−/− mice expand and mediate autoimmunity. Caspase-8–deficient Bim−/− T cells that escape negative selection in tcasp8−/−Bim−/− mice display elevated levels of necroptosis and impaired proliferation, and these defects lead to restrained autoimmunity and prolonged survival of tcasp8−/−Bim−/− mice.

Mentions: We also examined hematoxylin and eosin (HE)-stained sections of spleens, LN, lungs, livers, and kidneys from 13-mo-old tcasp8−/−Bim−/− mice and their control littermates. As previously reported (Bouillet et al., 1999), kidneys from Bim−/− mice presented with abnormally increased glomerular size and mesangial area, loss of open capillary loops, and accumulation of immune complexes compared with age-matched tcasp8−/− and WT controls (Fig. 7 A). Remarkably, this pathology caused by Bim deficiency was substantially diminished by concomitant loss of caspase-8 (in tcasp8−/−Bim−/− mice, Fig. 7 A). Further histological examination of tcasp8−/−Bim−/− mice indicated that infiltration of T and B cells into nonlymphoid organs was significantly reduced compared with both tcasp8−/− and Bim−/− mice (Figs. 7 A and S5 A). In addition, in contrast to Bim−/− mice, aged tcasp8−/−Bim−/− mice showed no glomerulonephritis, and their glomerular cell numbers were significantly reduced and indeed comparable to those of WT controls (Figs. 7 A and S5, A and B). Autoimmune glomerulonephritis in Bim−/− mice is accompanied by the accumulation of immune complexes in the kidneys (Bouillet et al., 1999). Anti-IgG staining of kidney sections indicated that the deposition of immune complexes in kidneys from tcasp8−/−Bim−/− mice was markedly reduced compared with kidneys from aged Bim−/− mice (Fig. 7 A).


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)

T cell–specific loss of caspase-8 inhibits the development of autoimmune disease in Bim−/− mice and increases their lifespan. (A) Representative immunohistochemical staining of lungs (left) and kidneys (right) from 13-mo-old mice of the indicated genotypes using HE, anti-CD3 antibody (red), and anti-B220 antibody (brown). Kidney sections were also stained with anti-IgG antibodies to assess the deposition of immune complexes (right). Bars, 100 µm. (B) Kaplan-Meier analysis representing the percent survival versus age in days of cohorts of WT (n = 15), tcasp8−/− (n = 25), Bim−/− (n = 20), and tcasp8−/−Bim−/− (n = 20) mice. The survival of tcasp8−/−Bim−/− mice was significantly extended compared with tcasp8−/− and Bim−/− mice (P < 0.05). (C) A model for the restrained autoimmunity of tcasp8−/−Bim−/− mice compared with Bim−/− littermates. Autoreactive T cells that escape negative selection in Bim−/− mice expand and mediate autoimmunity. Caspase-8–deficient Bim−/− T cells that escape negative selection in tcasp8−/−Bim−/− mice display elevated levels of necroptosis and impaired proliferation, and these defects lead to restrained autoimmunity and prolonged survival of tcasp8−/−Bim−/− mice.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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fig7: T cell–specific loss of caspase-8 inhibits the development of autoimmune disease in Bim−/− mice and increases their lifespan. (A) Representative immunohistochemical staining of lungs (left) and kidneys (right) from 13-mo-old mice of the indicated genotypes using HE, anti-CD3 antibody (red), and anti-B220 antibody (brown). Kidney sections were also stained with anti-IgG antibodies to assess the deposition of immune complexes (right). Bars, 100 µm. (B) Kaplan-Meier analysis representing the percent survival versus age in days of cohorts of WT (n = 15), tcasp8−/− (n = 25), Bim−/− (n = 20), and tcasp8−/−Bim−/− (n = 20) mice. The survival of tcasp8−/−Bim−/− mice was significantly extended compared with tcasp8−/− and Bim−/− mice (P < 0.05). (C) A model for the restrained autoimmunity of tcasp8−/−Bim−/− mice compared with Bim−/− littermates. Autoreactive T cells that escape negative selection in Bim−/− mice expand and mediate autoimmunity. Caspase-8–deficient Bim−/− T cells that escape negative selection in tcasp8−/−Bim−/− mice display elevated levels of necroptosis and impaired proliferation, and these defects lead to restrained autoimmunity and prolonged survival of tcasp8−/−Bim−/− mice.
Mentions: We also examined hematoxylin and eosin (HE)-stained sections of spleens, LN, lungs, livers, and kidneys from 13-mo-old tcasp8−/−Bim−/− mice and their control littermates. As previously reported (Bouillet et al., 1999), kidneys from Bim−/− mice presented with abnormally increased glomerular size and mesangial area, loss of open capillary loops, and accumulation of immune complexes compared with age-matched tcasp8−/− and WT controls (Fig. 7 A). Remarkably, this pathology caused by Bim deficiency was substantially diminished by concomitant loss of caspase-8 (in tcasp8−/−Bim−/− mice, Fig. 7 A). Further histological examination of tcasp8−/−Bim−/− mice indicated that infiltration of T and B cells into nonlymphoid organs was significantly reduced compared with both tcasp8−/− and Bim−/− mice (Figs. 7 A and S5 A). In addition, in contrast to Bim−/− mice, aged tcasp8−/−Bim−/− mice showed no glomerulonephritis, and their glomerular cell numbers were significantly reduced and indeed comparable to those of WT controls (Figs. 7 A and S5, A and B). Autoimmune glomerulonephritis in Bim−/− mice is accompanied by the accumulation of immune complexes in the kidneys (Bouillet et al., 1999). Anti-IgG staining of kidney sections indicated that the deposition of immune complexes in kidneys from tcasp8−/−Bim−/− mice was markedly reduced compared with kidneys from aged Bim−/− mice (Fig. 7 A).

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