γ-Interferon Signaling in Pancreatic β-Cells Is Persistent but Can Be Terminated by Overexpression of Suppressor of Cytokine Signaling-1

Chong, Mark M.W.; Thomas, Helen E.; Kay, Thomas W. H.

doi:10.2337/diabetes.50.12.2744

Cited by 42 publications

(65 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is also a substantial literature directly implicating the IFN-g signalling pathway in beta cell death, the critical destructive event at the heart of autoimmune diabetes. IFN-g drives a persistent signal in pancreatic beta cells that can be inhibited by overexpression of suppressor of cytokine signalling-1 (SOCS1) [17], and islet expression of SOCS1 was found to be protective in the rat insulin promoter-lymphocytic choriomeningitis virus (RIP-LCMV) mouse model of diabetes [18]. Both IFN-g -/- [16] and IFN-gR -/- [19] islets are killed less effectively in vitro by CD8 T cells [16] and cytokines [19].…”

Section: The Th1 Paradigm In T1dmentioning

confidence: 99%

CD4 T cell differentiation in type 1 diabetes

Walker

Herrath

2015

Clinical and Experimental Immunology

155

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

Section: The Th1 Paradigm In T1dmentioning

confidence: 99%

CD4 T cell differentiation in type 1 diabetes

Walker

Herrath

2015

Clinical and Experimental Immunology

155

113

View full text Add to dashboard Cite

show abstract

“…Islet cells were usually analyzed on the day of isolation. RNA extraction from islets and RT-PCR for members of the suppressors of cytokine signaling (SOCS) family were performed as previously described (23).…”

Section: Islet Isolationmentioning

confidence: 99%

Fas Is Detectable on β Cells in Accelerated, But Not Spontaneous, Diabetes in Nonobese Diabetic Mice

Darwiche

Chong

Santamaría

et al. 2003

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Fas (CD95) is a potential mechanism of pancreatic β cell death in type 1 diabetes. β cells do not constitutively express Fas but it is induced by cytokines. The hypothesis of this study is that Fas expression should be measurable on β cells for them to be killed by this mechanism. We have previously reported that up to 5% of β cells isolated from nonobese diabetic (NOD) mice are positive for Fas expression by flow cytometry using autofluorescence to identify β cells. We have now found that these are not β cells but contaminating dendritic cells, macrophages, and B lymphocytes. In contrast β cells isolated from NODscid mice that are recipients of T lymphocytes from diabetic NOD mice express Fas 18–25 days after adoptive transfer but before development of diabetes. Fas expression on β cells was also observed in BDC2.5, 8.3, and 4.1 TCR-transgenic models of diabetes in which diabetes occurs more rapidly than in unmodified NOD mice. In conclusion, Fas is observed on β cells in models of diabetes in which rapid β cell destruction occurs. Its expression is likely to reflect differences in the intraislet cytokine environment compared with the spontaneous model and may indicate a role for this pathway in β cell destruction in rapidly progressive models.

show abstract

“…During recent years, SOCS have emerged as potent modulators of additional pathways, such as those induced by insulin and growth hormone (GH) [6][7][8][9][10]. Concerning the pancreas, the role of SOCS proteins has so far been mainly studied in relation to the action of cytokines [11][12][13]. Among the different SOCS, SOCS3 has been the most intensively studied in pancreatic islets.…”

Section: Introductionmentioning

confidence: 99%

The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion

et al. 2010

View full text Add to dashboard Cite

Aims/hypothesis Suppressor of cytokine signalling (SOCS) proteins are powerful inhibitors of pathways involved in survival and function of pancreatic beta cells. Whereas SOCS1 and SOCS3 have been involved in immune and inflammatory processes, respectively, in beta cells, nothing is known about SOCS2 implication in the pancreas. Methods Transgenic (tg) mice were generated that constitutively produced SOCS2 in beta cells (βSOCS2) to define whether this protein is implicated in beta cell functioning and/or survival.Results Constitutive production of SOCS2 in beta cells leads to hyperglycaemia and glucose intolerance. This phenotype is not a consequence of decreased beta cell mass or inhibition of insulin synthesis. However, insulin secretion to various secretagogues is profoundly altered in intact animals and isolated islets. Interestingly, constitutive SOCS2 production dampens the rise in cytosolic free calcium concentration induced by glucose, while glucose metabolism is unchanged. Moreover, tg islets have a depletion in endoplasmic reticulum Ca 2+ stores, suggesting that SOCS2 interferes with calcium fluxes. Finally, inElectronic supplementary material The online version of this article

show abstract

γ-Interferon Signaling in Pancreatic β-Cells Is Persistent but Can Be Terminated by Overexpression of Suppressor of Cytokine Signaling-1

Cited by 42 publications

References 53 publications

CD4 T cell differentiation in type 1 diabetes

CD4 T cell differentiation in type 1 diabetes

Fas Is Detectable on β Cells in Accelerated, But Not Spontaneous, Diabetes in Nonobese Diabetic Mice

The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion

Contact Info

Product

Resources

About