Resistance of T-cells to apoptosis in autoimmune diabetic (NOD) mice is increased early in life and is associated with dysregulated expression of Bcl-x

Lamhamedi-Cherradi, Salah-Eddine; Luan, Jian-Jian; Eloy, Laure; Fluteau, G; Bach, Jean‐François; Garchon, Henri‐Jean

doi:10.1007/s001250050887

Cited by 50 publications

(27 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Apoptosis may represent one such parameter, as it regulates the homeostasis of the immune system (11) and can result in the deletion of autoreactive T cells in the thymus and periphery (12,13). NOD mice are defective in both central and peripheral tolerance, as NOD thymocytes show decreased susceptibility to Fas-dependent and Fas-independent apoptosis (14), and mitogen-activated NOD peripheral T cells become less sensitive to apoptosis after IL-2 withdrawal (15). NOD peripheral T cells are also less sensitive to glucocorticoid- (16), cyclophosphamide- (17) and gamma-irradiation-induced apoptosis (18), and display a decreased susceptibility to activation-induced cell death (AICD) in vitro (19,20).…”

Section: R Ecent Evidence Implicates a Crucial Role For Cd8mentioning

confidence: 99%

Perturbed Homeostasis of Peripheral T Cells Elicits Decreased Susceptibility to Anti-CD3-Induced Apoptosis in Prediabetic Nonobese Diabetic Mice

Yang

Hussain

et al. 2004

The Journal of Immunology

View full text Add to dashboard Cite

Activation-induced cell death (AICD) plays a key role in the homeostasis of the immune system. Autoreactive T cells are eliminated through AICD both from the thymus and periphery. In this study, we show that NOD peripheral T cells, especially CD8+ T cells, display a decreased susceptibility to anti-CD3-induced AICD in vivo compared with T cells from diabetes-resistant B6, nonobese diabetes-resistant, and NOD.B6Idd4 mice. The susceptibility of NOD CD8+ T cells to AICD varies in an age- and dose-dependent manner upon stimulation in vivo with either a mitogenic or nonmitogenic anti-CD3. NOD T cells preactivated by anti-CD3 in vivo are less susceptible than B6 T cells to TCR-induced AICD. Treatment of NOD mice with a mitogenic anti-CD3 depletes CD4+CD25−CD62L+ but not CD4+CD25+CD62L+ T cells, thereby resulting in an increase of the latter subset in the spleen. Treatment with a nonmitogenic anti-CD3 mAb delays the onset of T1D in 8.3 TCR transgenic NOD mice. These results demonstrate that the capacity of anti-CD3 to protect NOD mice from T1D correlates with its ability to perturb T cell homeostasis by inducing CD8+ T cell AICD and increasing the number of CD4+CD25+CD62L+ T cells in the periphery.

show abstract

Section: R Ecent Evidence Implicates a Crucial Role For Cd8mentioning

confidence: 99%

Perturbed Homeostasis of Peripheral T Cells Elicits Decreased Susceptibility to Anti-CD3-Induced Apoptosis in Prediabetic Nonobese Diabetic Mice

Yang

Hussain

et al. 2004

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Furthermore, apoptotic resistance may be an early phenotype of lymphoid lineages prior to disease initiation (Lamhamedi-Cherradi et al 1998).…”

Section: The Nod Mouse: a Spontaneous Mouse Model Of Type I Diabetesmentioning

confidence: 99%

Central role of defective apoptosis in autoimmunity

Kühtreiber

Hayashi²,

Dale

et al. 2003

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

Lymphocyte development, selection and education represent tightly controlled immune processes that normally prevent autoimmunity. Lymphocyte development likely induces cellular selection through apoptosis to remove potentially autoreactive cells. Dysregulated apoptosis, both interrupted as well as accelerated apoptosis, are now demonstrated as central defects in diverse murine autoimmune disease. In murine models of autoimmune lupus, mutations in cell death receptor Fas (CD95) and its ligand, FasL (CD95 L), have been identified. These errors create a lymphoid system resistant to apoptosis. In contrast, select lymphoid subpopulations of maturing autoimmune prone non-obese diabetic mice have identifiable and pathogenic T cells with both in vivo and in vitro heightened apoptosis after drug interventions. In part, these defects are due to faulty activation of transcription factors such as nuclear factor-B (NF-B) that normally protect against apoptotic death. The genetic basis of interrupted NF-B in pathogenic memory T cells in diabetes is attributable to a developmentally controlled gene defect in an essential subunit of the proteasome. No specific gene in most common forms of human autoimmune disease has yet been identified. Functional assays from diverse laboratories repeatedly demonstrate heightened apoptosis in multiple cellular signaling pathways for cell death, suggesting a common theme in disease causality.

show abstract

“…From data derived from fine mapping using linkage analysis and congenic mice, the IL-2 gene has been proposed as one of the Idd genes in NOD mice (52). It has recently been reported that resistance to T-cell apoptosis by deprivation of IL-2 is increased early in the lives of NOD mice (53). Lower production and/or activity of IL-2 in NOD mice may provide a suitable precondition for the expansion of autoreactive T-cells in autoimmune diabetes (52,54,55).…”

Section: Role Of Il-12 In Autoimmune Diabetesmentioning

confidence: 99%

Suppression and acceleration of autoimmune diabetes by neutralization of endogenous interleukin-12 in NOD mice.

et al. 2000

View full text Add to dashboard Cite

A corpus of evidence suggests that T-helper type 1 (Th1)-dependent cellular immunity plays a pivotal role in the pathogenesis of autoimmune diabetes. This study was intended to find ways to prevent the development of NOD diabetes using a neutralizing anti-interleukin (IL)-12 antibody (C17.8) that inhibits Th1 cell differentiation. When C17.8 was administered from 5 to 30 weeks of age, NOD mice exhibited suppression of both insulitis and diabetes. However, when C17.8 administration ceased at 15 weeks of age, 8 of 13 recipients showed diabetes at 30 weeks of age. These results suggest that IL-12 plays an important role not only in the development of effector cells but also in their activation. In contrast, when C17.8 was injected into 2-week-old female NOD mice for 6 consecutive days, all 16 recipients showed diabetes at 30 weeks of age, whereas 12 of 20 control mice became diabetic. This result suggests that depletion of endogenous IL-12 at a young age results in the enhancement of diabetes. Flow cytometric analysis indicated that activated memory T-cells were present in higher numbers after C17.8 treatment. Transfer of spleen cells from 15-week-old C17.8-treated NOD mice to NOD-scid mice resulted in an earlier onset and a higher incidence of diabetes. Furthermore, administration of C17.8 to 2-week-old NOD mice also resulted in a much earlier onset of diabetes. These results suggest that short-term treatment with anti-IL-12 antibody prohibits IL-2 production at a young age, which may influence the expansion and apoptosis of pathogenic T-cells, resulting in the acceleration of autoimmune diabetes.

show abstract

Resistance of T-cells to apoptosis in autoimmune diabetic (NOD) mice is increased early in life and is associated with dysregulated expression of Bcl-x

Cited by 50 publications

References 42 publications

Perturbed Homeostasis of Peripheral T Cells Elicits Decreased Susceptibility to Anti-CD3-Induced Apoptosis in Prediabetic Nonobese Diabetic Mice

Perturbed Homeostasis of Peripheral T Cells Elicits Decreased Susceptibility to Anti-CD3-Induced Apoptosis in Prediabetic Nonobese Diabetic Mice

Central role of defective apoptosis in autoimmunity

Suppression and acceleration of autoimmune diabetes by neutralization of endogenous interleukin-12 in NOD mice.

Contact Info

Product

Resources

About