Diabetes in non‐obese diabetic mice is not associated with quantitative changes in CD4+ CD25+ Foxp3+ regulatory T cells

Mellanby, Richard J.; Thomas, David; Phillips, Jenny; Cooke, Anne

doi:10.1111/j.1365-2567.2007.02546.x

Cited by 90 publications

(101 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since anti-CD25 antibodies do not always deplete CD25 + T cells [27], but rather inhibit their function [37], the cytokine environment might be less favourable for expansion of the CD25 − FOXP3 + T cells [39]. Reactive changes in CD25, CD62L and FOXP3 as phenotypic markers of putative Treg have been previously observed with immunomodulatory agents such as Cy, anti-IL-2, anti-CD25 and anti-CD3, and have been generally associated with positive outcome of immunomodulation in NOD mice [4,5,16,28]. A similar reactive increase in FOXP3 expression has recently been associated with beneficial effects of Treg activation achieved by several immunomodulatory modalities, including IL-2/IL-2 antibody complexes, anti-thymocyte globulin, complete Freund's adjuvant, vasoactive intestinal peptide and rapamycin [18,[40][41][42][43][44].…”

Section: Discussionmentioning

confidence: 98%

“…Impact of cyclophosphamide and IL2-cas on diabetes in NOD mice In view of the evidence that IL2-cas induces apoptosis in CD25 + T cells and decreases effector activity, the fusion protein was evaluated in NOD mice in vivo. On the one hand, an agent that mediates targeted killing of CD25 + T cells is expected to precipitate early onset of diabetes similar to cyclophosphamide [4][5][6] and anti-CD25 antibodies [27,28]. On the other hand, decreased activity of reactive cells suggests that the fusion protein might ameliorate the course of insulitis as observed with diphtheria toxin in NOD mice [20] and IL2-cas in inflammatory colitis [22,23,25].…”

Section: Il2-cas Suppresses Effector Cellsmentioning

confidence: 99%

See 1 more Smart Citation

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

Yarkoni¹,

Kaminitz

Sagiv³

et al. 2009

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis Interruption of IL-2 signalling is an attractive therapeutic target in autoimmune disorders. In this study we evaluated the effect of a fusion protein composed of IL-2 and caspase-3 (IL2-cas) on NOD mice, as compared with disease induction by cyclophosphamide. Methods IL2-cas was assessed in NOD mice at various ages and in conjunction with cyclophosphamide administration. The effect of IL2-cas on diabetogenic cells was evaluated in adoptive transfer experiments and in cell suspension in vitro. Results IL2-cas induced apoptosis in T cells expressing the α chain of the IL-2 receptor (cluster of differentiation [CD] 25) in vitro, with superior survival of T cells expressing CD4 and forkhead box P3 (FOXP3). The fusion protein decreased mixed lymphocyte reactivity, and pretreatment with IL2-cas decreased the efficacy of adoptive transfer of diabetes into NOD severe combined immunodeficiency mice. Administration of one dose of IL2-cas decreased the incidence of diabetes in NOD mice, showing a superior beneficial effect when administered at young age, and effectively blocked induction of hyperglycaemia by cyclophosphamide, reducing the severity of islet inflammation. Administration of IL2-cas caused an acute increase in CD25 -FOXP3 + T cells in the lymph nodes, pancreas and thymus in NOD mice, with similar effects in wild-type mice. Administration of IL2-cas after onset of hyperglycaemia resulted in superior survival. Conclusions/interpretation Targeted elimination of cells expressing the IL-2 receptor by this fusion protein disrupts the autoimmune pathogenesis in prediabetic and diabetic NOD mice, despite depletion of CD25 + regulatory T cells. Furthermore, this particular fusion protein is permissive to the development of FOXP3 + T cells that might contribute to protracted protection from the progression of insulitis and overt hyperglycaemia.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Il2-cas Suppresses Effector Cellsmentioning

confidence: 99%

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

Yarkoni¹,

Kaminitz

Sagiv³

et al. 2009

Diabetologia

View full text Add to dashboard Cite

show abstract

“…As they are FoxP3 + , these regulatory T cells are most consistent with 'natural' regulatory T cells, which characteristically exert their suppressive effects in an IL-10-independent but contact-dependent manner. While development of diabetes in NOD mice is not associated with changes in the numbers of natural regulatory T cells, 30,31 there is mounting evidence that development of type 1 diabetes is associated with a qualitative defect in regulatory T-cell function. The suppressive capability of natural regulatory T cells of NOD mice decreases with age 32 and T-regulatory cells expanded from 4-week-old NOD mice are more protective against diabetes than those expanded from older NOD mice.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of type 1 diabetes in filaria‐infected non‐obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3⁺ regulatory T cells

Hübner¹,

Mitre³

2009

Immunology

115

103

View full text Add to dashboard Cite

Summary We sought to determine whether Litomosoides sigmodontis, a filarial infection of rodents, protects against type 1 diabetes in non‐obese diabetic (NOD) mice. Six‐week‐old NOD mice were sham‐infected or infected with either L3 larvae, adult male worms, or adult female worms. Whereas 82% of uninfected NOD mice developed diabetes by 25 weeks of age, no L. sigmodontis‐infected mice developed disease. Although all mice had evidence of ongoing islet cell inflammation by histology, L. sigmodontis‐infected mice had greater numbers of total islets and non‐infiltrated islets than control mice. Protection against diabetes was associated with a T helper type 2 (Th2) shift, as interleukin‐4 (IL‐4) and IL‐5 release from α‐CD3/α‐CD28‐stimulated splenocytes was greater in L. sigmodontis‐infected mice than in uninfected mice. Increased circulating levels of insulin‐specific immunoglobulin G1, showed that this Th2 shift occurs in response to one of the main autoantigens in diabetes. Multicolour flow cytometry studies demonstrated that protection against diabetes in L. sigmodontis‐infected NOD mice was associated with significantly increased numbers of splenic CD4+ CD25+ FoxP3+ regulatory T cells. Interestingly, injection of crude worm antigen into NOD mice also resulted in protection against type 1 diabetes, though to a lesser degree than infection with live L. sigmodontis worms. In conclusion, these studies demonstrate that filarial worms can protect against the onset of type 1 diabetes in NOD mice. This protection is associated with a Th2 shift, as demonstrated by cytokine and antibody production, and with an increase in CD4+ CD25+ FoxP3+ regulatory T cells.

show abstract

“…How, when, and why peripheral immunological tolerance is progressively lost and the disease is initiated, is a matter of investigation. One of was challenged and it was suggested that the decline may reflect contamination of the CD4 + CD25 + "Treg" cells with Foxp3 − cells that lack regulatory capacity [7]. However, control of diabetogenic T-cell activity may still be defective since conventional T (Tconv) cells from older NOD mice were found to be relatively resistant to suppression by Treg cells [5,6,8].…”

Section: Introductionmentioning

confidence: 99%

Increased thymic development of regulatory T cells in NOD mice is functionally dissociated from type I diabetes susceptibility

et al. 2013

View full text Add to dashboard Cite

Regulatory T (Treg) lymphocytes play a central role in the control of autoimmune pathology. Any alteration in Treg-cell biology in mouse strains used for the study of these disorders therefore raises the question of its direct link with disease susceptibility. Paradoxically, in non-obese diabetic (NOD) mice increased numbers of Treg cells develop in the thymus. In this report we identify a locus of <7 Mbp that quantitatively controls Treg-cell development in the thymus of the NOD mouse. This 'Trd1' region is located centromeric to the H2 complex on chromosome 17 and does not include genes encoding classical MHC molecules. The genomic region identified here contains the Idd16 diabetes susceptibility locus and the use of congenic mouse strains allowed us to investigate the potential link between quantitatively altered thymic Treg cells and diabetes susceptibility. Hybrid mice present similar levels of thymic Treg cells as B6 animals but they developed diabetes with the same kinetics as NOD mice. Therefore, the increased Treg-cell development in NOD mice controlled by Trd1 is functionally dissociated from the susceptibility of NOD to diabetes. Keywords: Differentiation r Regulatory T (Treg) cells r Thymus r T1DAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionType I diabetes (T1D) is an autoimmune disease caused by destruction of insulin-producing pancreatic β cells. How, when, and why peripheral immunological tolerance is progressively lost and the disease is initiated, is a matter of investigation. One of Correspondence: Dr. Paola Romagnoli e-mail: Paola.Romagnoli@inserm.fr the major players in the maintenance of peripheral tolerance are natural occurring CD4 + (CD25 + )Foxp3 + regulatory T (Treg) cells [1]. Treg cells can prevent diabetes and even reverse established pathology in non-obese diabetic (NOD) mice [2][3][4]. Interestingly, an age-dependent decline in the in vitro and in vivo function of NOD CD4 + CD25 + Treg cells was reported [5,6]. This conclusion * These authors contributed equally to this work.www.eji-journal.eu Eur. J. Immunol. 2013. 43: 1356-1362 Molecular immunology 1357 was challenged and it was suggested that the decline may reflect contamination of the CD4 + CD25 + "Treg" cells with Foxp3 − cells that lack regulatory capacity [7]. However, control of diabetogenic T-cell activity may still be defective since conventional T (Tconv) cells from older NOD mice were found to be relatively resistant to suppression by Treg cells [5,6,8]. Importantly, a recent study showed that the TCR-repertoire of Treg cells may be less diverse in NOD than in B6 mice [9]. It remains therefore unclear if the NOD Treg-cell population would have a functional in vivo defect. Natural Treg cells are generated in the thymus where the processes of positive and negative selection shape their autospecific TCR repertoire [10]. Two groups have shown quantitative differences in Treg-cell development in NOD mice [11,12]. Feuerer et al. [11] reported incr...

show abstract

Diabetes in non‐obese diabetic mice is not associated with quantitative changes in CD4⁺ CD25⁺ Foxp3⁺ regulatory T cells

Cited by 90 publications

References 46 publications

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

Inhibition of type 1 diabetes in filaria‐infected non‐obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3⁺ regulatory T cells

Increased thymic development of regulatory T cells in NOD mice is functionally dissociated from type I diabetes susceptibility

Contact Info

Product

Resources

About

Diabetes in non‐obese diabetic mice is not associated with quantitative changes in CD4+ CD25+ Foxp3+ regulatory T cells

Cited by 90 publications

References 46 publications

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

Inhibition of type 1 diabetes in filaria‐infected non‐obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3+ regulatory T cells

Increased thymic development of regulatory T cells in NOD mice is functionally dissociated from type I diabetes susceptibility

Contact Info

Product

Resources

About

Diabetes in non‐obese diabetic mice is not associated with quantitative changes in CD4⁺ CD25⁺ Foxp3⁺ regulatory T cells

Inhibition of type 1 diabetes in filaria‐infected non‐obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3⁺ regulatory T cells