Loss of parity between IL-2 and IL-21 in the NOD Idd3 locus

McGuire, Helen M.; Vogelzang, Alexis; Hill, Natasha J.; Flodström‐Tullberg, Malin; Sprent, Jonathan; King, Charles M.

doi:10.1073/pnas.0903561106

Cited by 57 publications

(62 citation statements)

References 39 publications

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“…IL-21 is familiar to the diabetes community as a candidate gene at the diabetes susceptibility locus Idd3 [73][74][75], and levels of IL-21 mRNA have been shown to increase during diabetes development in mice [76][77][78] (Table 1). IL-21 is a member of the common-g chain receptor family of cytokines that includes IL-2, IL-4, IL-7, IL-9 and IL-15.…”

Section: Il-21 Is Required For Autoimmune Diabetes In Micementioning

confidence: 99%

CD4 T cell differentiation in type 1 diabetes

Walker

Herrath

2015

Clinical and Experimental Immunology

152

113

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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.

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Section: Il-21 Is Required For Autoimmune Diabetes In Micementioning

confidence: 99%

CD4 T cell differentiation in type 1 diabetes

Walker

Herrath

2015

Clinical and Experimental Immunology

152

113

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“…Intronic IL-4Ra (pre-mRNA) was measured by an allele-specific pyrosequencing assay as described previously (45). Pyrosequencing was performed on cDNA synthesized from the DNase-treated RNA.…”

Section: Measurement Of Il-4r By Quantitative Pcr and Pyrosequencingmentioning

confidence: 99%

IL-21 and IL-4 Collaborate To Shape T-Dependent Antibody Responses

McGuire

Vogelzang

Warren

et al. 2015

The Journal of Immunology

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The selection of affinity-matured Ab-producing B cells is supported by interactions with T follicular helper (Tfh) cells. In addition to cell surface–expressed molecules, cytokines produced by Tfh cells, such as IL-21 and IL-4, provide B cell helper signals. In this study, we analyze how the fitness of Th cells can influence Ab responses. To do this, we used a model in which IL-21R–sufficient (wild-type [WT]) and –deficient (Il21r−/−) Ag-specific Tfh cells were used to help immunodeficient Il21r−/− B cells following T-dependent immunization. Il21r−/− B cells that had received help from WT Tfh cells, but not from Il21r−/− Tfh cells, generated affinity-matured Ab upon recall immunization. This effect was dependent on IL-4 produced in the primary response and associated with an increased fraction of memory B cells. Il21r−/− Tfh cells were distinguished from WT Tfh cells by a decreased frequency, reduced conjugate formation with B cells, increased expression of programmed cell death 1, and reduced production of IL-4. IL-21 also influenced responsiveness to IL-4 because expression of both membrane IL-4R and the IL-4–neutralizing soluble (s)IL-4R were reduced in Il21r−/− mice. Furthermore, the concentration of sIL-4R was found to correlate inversely with the amount of IgE in sera, such that the highest IgE levels were observed in Il21r−/− mice with the least sIL-4R. Taken together, these findings underscore the important collaboration between IL-4 and IL-21 in shaping T-dependent Ab responses.

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“…It has also been shown that ARNTL2 binds to the promoter of the interleukin-21 (Il-21) gene, which itself controls the proliferation of immune cells [47]. Il-21 is located in the type 1 diabetes locus Idd3 [48]. The interaction is absent in the NOD mouse but present in non-diabetic mouse strains (C57BL/6, C3H/HeJ).…”

Section: Arntl2 Is a Candidate Gene For Type 1 Diabetesmentioning

confidence: 99%

Circadian rhythm‐related genes: implication in autoimmunity and type 1 diabetes

Lebailly

Rogner

2015

Diabetes Obesity Metabolism

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Recent gene association and functional studies have proven the implication of several circadian rhythm-related genes in diabetes. Diabetes has been related to variation in central circadian regulation and peripheral oscillation. Different transcriptional regulators have been identified. Circadian genes are clearly implicated in metabolic pathways, pancreatic function and in type 2 diabetes. Much less evidence has been shown for the link between circadian regulation and type 1 diabetes. The hypothesis that circadian genes are involved in type 1 diabetes is reinforced by findings that the immune system undergoes circadian variation and that several autoimmune diseases are associated with circadian genes. Recent findings in the non-obese diabetic mouse model pinpoint to specific mechanisms controlling type 1 diabetes by the clock-related gene Arntl2 in the immune system. Keywords: circadian rhythm, cytokine, immune system, transcription factor, type 1 diabetes Date submitted 10 April 2015; date of final acceptance 5 May 2015 Circadian Genes and DiabetesThere is growing evidence about the implication of the circadian rhythm in diabetes development [1]. Studies in mice have shown that the disruption of circadian rhythms can accelerate diabetes and -cell loss [2]. In humans a link between the central circadian rhythm regulation and glucose homeostasis has been suggested by findings such as the polymorphism in MTNR1B, encoding the melatonin receptor 1B, that increases the risk for type 2 diabetes [3].Transcription and translation of core clock components circadian locomotor output cycles kaput (CLOCK), aryl hydrocarbon receptor nuclear translocator-like 1 (ARNTL1), aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2), period circadian proteins (PER1, PER2, PER3) and Cryptochromes (CRY1 and CRY2) play a pivotal role in rhythm generation in the suprachiasmatic nucleus, which is the site of the master circadian oscillator in mammals, but also in the control of peripheral oscillations.The direct relation of CLOCK-related genes in diabetes has already been shown [4]. ARNTL1, which is also called brain and muscle ARNT-like 1 (BMAL1) or member of PAS superfamily 3 (MOP3), has been genetically linked to hypertension and type 2 diabetes in humans [5]. Knockout mice for Arntl1 and Clock exhibited a role for the -cell clock in coordinating insulin secretion with the sleep-wake cycle, and revealed that ablation of the pancreatic clock can trigger the onset of diabetes mellitus [6]. The major circadian pacemaker ARNTL1 has in addition been associated with susceptibility to gestational diabetes mellitus [7]. CRY, another component of the core clock, is required for the regulation of inflammatory cytokines via the NF-kappaB Other homologous genes of the family of basic helix-loophelix transcription factors, such as the dioxin-receptor encoding gene AHR [10], ARNT [11] have been associated with diabetes. The Aryl Hydrocarbon Receptor (AHR) is a cytosolic transcription factor that is normally inactive, bound to several co-cha...

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Loss of parity between IL-2 and IL-21 in the NOD Idd3 locus

Cited by 57 publications

References 39 publications

CD4 T cell differentiation in type 1 diabetes

CD4 T cell differentiation in type 1 diabetes

IL-21 and IL-4 Collaborate To Shape T-Dependent Antibody Responses

Circadian rhythm‐related genes: implication in autoimmunity and type 1 diabetes

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