Gamma Interferon Paradoxically Inhibits the Development of Diabetes in the NOD Mouse

Sobel, Douglas O.; Han, Jaeseok; Williams, Joy; Yoon, Ji‐Won; Lee, Youn-Jung; Ahvazi, Behrouz

doi:10.1006/jaut.2002.0604

Cited by 42 publications

(36 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This may not be surprising as each of these cytokines is known to stimulate T cell AICD (44 -52), and a decrease in their level of production would be expected to mediate the decreased susceptibility of NOD T cells to AICD in vivo. Moreover, administration of each of these cytokines to NOD mice protects them from T1D, which may occur in part by restoring the susceptibility of CD8 ϩ T cells to AICD and depletion, as described for IFN-␥ (50).…”

Section: Discussionmentioning

confidence: 96%

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: Discussionmentioning

confidence: 96%

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

“…B, IL-17 production from polarized cells from CFA-immunized NOD mice was blocked by anti-IL-17 Ab when added at the beginning of culture to neutralize IL-17 production. C, After 4 d, cells (10 3 10 mice has been shown to reduce the chance of diabetes development (31). Also, Lee et al (12,13) found that NK cells mediate the protective effects of CFA through secretion of IFN-g.…”

Section: Discussionmentioning

confidence: 99%

Th17 Polarized Cells from Nonobese Diabetic Mice Following Mycobacterial Adjuvant Immunotherapy Delay Type 1 Diabetes

Nikoopour¹,

Schwartz²,

Huszarik³

et al. 2010

The Journal of Immunology

View full text Add to dashboard Cite

IL-17–producing T cells are regarded as potential pathogenic T cells in the induction of autoimmune diseases. Previously, we have shown that injection of adjuvants containing Mycobacterium, such as CFA or bacillus Calmette-Guérin, can prevent type 1 diabetes in NOD mice. We injected NOD mice with mycobacterial products s.c. and analyzed the IL-17–producing cells from the draining lymph nodes and spleen by restimulating whole-cell populations or CD4+ T cells in vitro with or without IL-17–polarizing cytokines. Mice receiving CFA had a concomitant rise in the level of IL-17, IL-22, IL-10, and IFN-γ in the draining lymph node and spleen. Adoptive transfer of splenocytes from CFA-injected NOD mice polarized with TGF-β plus IL-6 or IL-23 delayed the development of diabetes in recipient mice. IL-17–producing cells induced by CFA maintained their IL-17–producing ability in the recipient mice. Injection of CFA also changed the cytokine profile of cells in pancreatic tissue by increasing IL-17, IL-10, and IFN-γ cytokine gene expression. We suggest that the rise in the level of IL-17 after adjuvant therapy in NOD mice has a protective effect on type 1 diabetes development.

show abstract

“…In fact, deficiency in IFN-g [31] or the b chain of its receptor [30] surprisingly leads to only a mild delay in diabetes development. Deficiency of IL-4 failed to exacerbate disease in NOD mice [32], while injection of recombinant IFN-g did not accelerate diabetes [33] and, indeed, could even inhibit it [34]. In certain experimental settings, the regulatory T cells protecting from diabetes actually required IFN-g [35].…”

Section: Evidence Against the Th1 Paradigmmentioning

confidence: 98%

CD4 T cell differentiation in type 1 diabetes

Walker

Herrath

2015

Clinical and Experimental Immunology

153

113

View full text Add to dashboard Cite

SummarySusceptibility to type 1 diabetes is associated strongly with human leucocyte antigen (HLA) genes, implicating T cells in disease pathogenesis. In humans, CD8 T cells predominantly infiltrate the islets, yet their activation and propagation probably requires CD4 T cell help. CD4 T cells can select from several differentiation fates following activation, and this choice has profound consequences for their subsequent cytokine production and migratory potential. In turn, these features dictate which other immune cell types T cells interact with and influence, thereby determining downstream effector functions. Obtaining an accurate picture of the type of CD4 T cell differentiation associated with a particular immune-mediated disease therefore constitutes an important clue when planning intervention strategies. Early models of T cell differentiation focused on the dichotomy between T helper type 1 (Th1) and Th2 responses, with type 1 diabetes (T1D) being viewed mainly as a Th1-mediated pathology. However, several additional fate choices have emerged in recent years, including Th17 cells and follicular helper T cells. Here we revisit the issue of T cell differentiation in autoimmune diabetes, highlighting new evidence from both mouse models and patient samples. We assess the strengths and the weaknesses of the Th1 paradigm, review the data on interleukin (IL)-17 production in type 1 diabetes and discuss emerging evidence for the roles of IL-21 and follicular helper T cells in this disease setting. A better understanding of the phenotype of CD4 T cells in T1D will undoubtedly inform biomarker development, improve patient stratification and potentially reveal new targets for therapeutic intervention.

show abstract

Gamma Interferon Paradoxically Inhibits the Development of Diabetes in the NOD Mouse

Cited by 42 publications

References 56 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

Th17 Polarized Cells from Nonobese Diabetic Mice Following Mycobacterial Adjuvant Immunotherapy Delay Type 1 Diabetes

CD4 T cell differentiation in type 1 diabetes

Contact Info

Product

Resources

About