Tolerance to Islet Antigens and Prevention from Diabetes Induced by Limited Apoptosis of Pancreatic β Cells

Hugues, Stéphanie; Mougneau, Evelyne; Ferlin, Walter; Jeske, Dirk; Hofman, Paul; Homann, Dirk; Beaudoin, Lucie; Schrike, Corinne; Herrath, Matthias von; Lehuen, Agnès; Glaichenhaus, Nicolas

doi:10.1016/s1074-7613(02)00273-x

Cited by 146 publications

(138 citation statements)

References 48 publications

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“…Nevertheless, previous studies have demonstrated that DCs are the predominant cell type that presents islet-derived self-antigens (24)(25)(26)(27). To determine whether the cells responsible for presentation here were DCs, CD11c-DTR3RIP-OVA lo bone marrow chimeras were generated.…”

Section: Ctl Damage Induces Antigen Releasementioning

confidence: 99%

Tissue destruction caused by cytotoxic T lymphocytes induces deletional tolerance

Parish

Waithman

Davey

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Autoimmune diseases tend to be chronic and progressive, but how these responses are sustained is not clear. One cell type that might contribute to autoimmunity is the cytotoxic T lymphocyte (CTL), which, as a consequence of causing tissue destruction and production of cytokines, could provide a sustained supply of antigen and inflammatory signals for dendritic cells to maintain immune stimulation. Here we examined whether such CTL-mediated tissue damage alone could provide antigen in the right context to recruit immune effectors and sustain autoimmunity. We show that while CTL-mediated tissue damage caused the release of self-antigens that stimulated the proliferation of naive autoreactive CD8 ؉ T cells, such responses failed to precipitate disease and, instead, led to deletional tolerance. These findings indicate that despite the capacity of CTLs to produce inflammatory cytokines and to cause tissue damage, their responses are not sustaining, but instead favor induction of self-tolerance.antigen presentation ͉ apoptosis ͉ autoimmunity ͉ CTL ͉ T cell

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Section: Ctl Damage Induces Antigen Releasementioning

confidence: 99%

Tissue destruction caused by cytotoxic T lymphocytes induces deletional tolerance

Parish

Waithman

Davey

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Activation of caspases may be achieved by several molecular pathways; the best known stimuli triggering the caspase cascade are stimulation of Fas or TNF receptors, release of cytochrome c from the cellular mitochondria, and exposure to granzymes, which are secreted by cytotoxic T cells (3,12,31,37,54). Detailed research on the mechanisms controlling caspase activity will provide better insight into the pathogenesis of autoimmune diseases with special reference to estrogen deficiency.…”

mentioning

confidence: 99%

Novel Role for RbAp48 in Tissue-Specific, Estrogen Deficiency-Dependent Apoptosis in the Exocrine Glands

Ishimaru

Arakaki

Omotehara

et al. 2006

Molecular and Cellular Biology

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Although tissue-specific apoptosis in the exocrine glands in estrogen-deficient mice may contribute to the development of autoimmune exocrinopathy, the molecular mechanism responsible for tissue-specific apoptosis remains obscure. Here we show that RbAp48 overexpression induces p53-mediated apoptosis in the exocrine glands caused by estrogen deficiency. RbAp48-inducible transfectant results in rapid apoptosis with p53 phosphorylation (Ser9) and ␣-fodrin cleavage. Reducing the expression of RbAp48 through small interfering RNA inhibits the apoptosis. Prominent RbAp48 expression with apoptosis was observed in the exocrine glands of C57BL/6 ovariectomized (OVX) mice but not in OVX estrogen receptor ␣ ؊/؊ , p53 ؊/؊ , and E2F-1 ؊/؊ mice. Indeed, transgenic expression of the RbAp48 gene induced apoptosis in the exocrine glands but not in other organs. These findings indicate that estrogen deficiency initiates p53-mediated apoptosis in the exocrine gland cells through RbAp48 overexpression and exerts a possible gender-based risk of autoimmune exocrinopathy in postmenopausal women.

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“…This limited and arrested in vivo proliferation followed by T-cell deletion has been associated with induction of tolerance. [18][19][20] Activated splenic CD4 + KJ1-26 + cells after intrasplenic immunization with T/SA-OVA secrete IL-10 and IL-4 and not IFN-g…”

Section: Splenic Cd11c and Cd4 T-cell Interaction And Tumour Cell Vacmentioning

confidence: 99%

“…It is controversial whether CD8 + T-cell tolerance [18][19][20] results from an interaction between CD8 + T cells and immature CD11c + cells 21 or quite the reverse, with mature CD11c + cells. 22 However, in both cases, one can assume that CD4 + T-cell tolerance ensues from an encounter with immature CD11c + cells and this may generate regulatory T cells.…”

Section: Introductionmentioning

confidence: 99%

In vivo splenic CD11c cells downregulate CD4 T-cell response thereby decreasing systemic immunity to gene-modified tumour cell vaccine

et al. 2007

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One of the factors influencing the efficacy of tumour cell vaccines is the site of immunization. We have shown previously that gene-modified vaccines delivered directly inside the spleen induced antigen cross-presentation by splenic antigen-presenting cells (not B cells). Here, we examined the interaction between splenic CD11c + cells and antigen-specific CD4 + T cells. We used tumour cells expressing ovalbumin (OVA), a situation where CD4 + T-cell help is required for the generation of a cytotoxic T lymphocyte response. Using in vivo bioluminescence imaging of luciferase-expressing EL4-OVA cells, we could demonstrate that tumour cells were located exclusively inside the spleen following intrasplenic injection. We showed that after intrasplenic immunization with T/SA-OVA cells, splenic class I + class II + CD11c + cells engulfed and presented in vivo the OVA class I-restricted peptide SIINFEKL. However, in vivo previously adoptively transferred 5,6-carboxy-succinimidyl-fluorescein-ester-labelled transgenic CD4 + KJI-26 + cells specific for the class II OVA 323-339 peptide underwent abortive proliferation in the spleen. These CD4 + KJI-26 + cells were only transiently activated and produced IL-10 and IL-4 and not IFN-g. It appears that splenic CD11c + cells can downregulate splenic specific CD4 + T-cell response thereby leading to a decrease in antitumour systemic immunity.

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Tolerance to Islet Antigens and Prevention from Diabetes Induced by Limited Apoptosis of Pancreatic β Cells

Cited by 146 publications

References 48 publications

Tissue destruction caused by cytotoxic T lymphocytes induces deletional tolerance

Tissue destruction caused by cytotoxic T lymphocytes induces deletional tolerance

Novel Role for RbAp48 in Tissue-Specific, Estrogen Deficiency-Dependent Apoptosis in the Exocrine Glands

In vivo splenic CD11c cells downregulate CD4 T-cell response thereby decreasing systemic immunity to gene-modified tumour cell vaccine

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