Dynamics of Pathogenic and Suppressor T Cells in Autoimmune Diabetes Development

Gregori, Silvia; Giarratana, Nadia; Smiroldo, Simona; Adorini, Luciano

doi:10.4049/jimmunol.171.8.4040

Cited by 219 publications

(244 citation statements)

References 53 publications

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“…This resistance of T eff to inhibition by T reg and TGF-␤ may help explain the increased autoimmunity seen in Cbl-b Ϫ/Ϫ mice. Furthermore, in light of similar findings in both aged NOD mice and T eff exposed to LPS-treated dendritic cells, our present findings suggest that resistance to regulation may be a relevant mechanism in both normal immune function and autoimmunity (12,13).…”

supporting

confidence: 51%

Resistance to CD4+CD25+ Regulatory T Cells and TGF-β in Cbl-b−/− Mice

Wohlfert

Callahan

Clark

2004

The Journal of Immunology

117

132

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Cbl-b−/− mice have signaling defects that result in CD28-independent T cell activation, increased IL-2 production, hyper-reactive T cells, and increased autoimmunity. Although the increased autoimmunity in these mice is believed to result from the hyper-reactive T cells, the mechanisms leading from T cell hyper-reactivity to autoimmunity remain unclear. Specifically, the function and interaction of CD4+CD25+ regulatory T cells (Treg) and CD4+CD25− effector T cells (Teff) in Cbl-b−/− mice have not been examined. We now report that Cbl-b−/− CD4+CD25+ Treg exhibit normal regulatory function in vitro. In contrast, the in vitro response of Cbl-b−/− CD4+CD25− Teff is abnormal, in that it is not inhibited by either Cbl-b−/− or wild-type Treg. This resistance of Cbl-b−/− Teff to in vitro regulation is seen at the levels of both DNA synthesis and cell division. In addition to this resistance to CD4+CD25+ Treg, Cbl-b−/− Teff demonstrate in vitro resistance to inhibition by TGF-β. This second form of resistance in Cbl-b−/− Teff is seen despite the expression of normal levels of type II TGF-β receptors and normal levels of phosphorylated Smad3 after TGF-β stimulation. Coupled with recent reports of resistance to Treg in Teff exposed to LPS-treated dendritic cells, our present findings suggest that resistance to regulation may be a relevant mechanism in both normal immune function and autoimmunity.

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supporting

confidence: 51%

Resistance to CD4+CD25+ Regulatory T Cells and TGF-β in Cbl-b−/− Mice

Wohlfert

Callahan

Clark

2004

The Journal of Immunology

117

132

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“…NOD mice have a defect in thymic negative selection of self-reactive thymocytes that results in loss of tolerance to autoantigens [21]. In addition, NOD mice generate low numbers of regulatory T cells [22] and the suppressive effect of these cells decreases in an age-dependent manner [23]. Our data have demonstrated that systemic treatment with gal-9 can downregulate Th1-cell numbers and T-cell proliferative responses in NOD mice.…”

Section: Gal-9 Treatment Does Not Induce An Active Tolerance In Nod Micementioning

confidence: 59%

Attenuation of Th1 response through galectin‐9 and T‐cell Ig mucin 3 interaction inhibits autoimmune diabetes in NOD mice

2009

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Galectin-9 (gal-9), widely expressed in many tissues, regulates Th1 cells and induces their apoptosis through its receptor, T-cell Ig mucin 3, which is mainly expressed on terminally differentiated Th1 cells. Type 1 diabetes is a Th1-dominant autoimmune disease that specifically destroys insulin-producing b cells. To suppress the Th1 immune response in the development of autoimmune diabetes, we overexpressed gal-9 in NOD mice by injection of a plasmid encoding gal-9. Mice treated with gal-9 plasmid were significantly protected from diabetes and showed less severe insulitis compared with controls. Flow cytometric analyses in NOD-T1/2 double transgenic mice showed that Th1-cell population in spleen, pancreatic lymph node and pancreas was markedly decreased in gal-9 plasmidtreated mice, indicating a negative regulatory role of gal-9 in the development of pathogenic Th1 cells. Splenocytes from gal-9 plasmid-treated mice were less responsive to mitogenic stimulation than splenocytes from the control group. However, adoptive transfer of splenocytes from gal-9-treated or control mice caused diabetes in NOD/SCID recipients with similar kinetics, suggesting that gal-9 treatment does not induce active tolerance in NOD mice. We conclude that gal-9 may downregulate Th1 immune response in NOD mice and could be used as a therapeutic target in autoimmune diabetes.Key words: Galectin-9 . Th1 . T-cell Ig mucin 3 . Type 1 diabetes IntroductionWhen CD4 1 Th cells interact with class II MHC-peptide complex and costimulatory molecules on APC, they differentiate into several effector subsets. There are two major Th subsets that have unique patterns of cytokine secretion and different functional properties. Th1 cells produce cytokines such as IFN-g, IL-2, TNF-a and lymphotoxin that are commonly associated with cellmediated immune responses against intracellular pathogens, delayed-type hypersensitivity and induction of organ-specific autoimmune diseases. Th2 cells produce cytokines such as IL-4, IL-5, IL-10 and IL-13 that are crucial for controlling extracellular helminth infections and promoting atopic and allergic diseases [1,2].Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disease that selectively destroys the insulin-producing b cells in the pancreas. NOD mice spontaneously develop autoimmune diabetes with immunopathological features resembling those of human disease and can be used as an animal model to study the pathogenesis of T1D. Previous studies have demonstrated that transfer of NOD CD4 1 T cells to immunodeficient NOD/SCID mice can induce diabetes in those recipients, indicating that CD4 1 T cells play an important role in the pathogenesis of diabetes [3,4] [12]. Previous approaches using TIM-3-Ig fusion protein to interrupt the interactions between TIM-3 and its ligand in vivo resulted in hyperproliferation of Th1 cells and release of Th1-related cytokines [13]. TIM-3 ligand was subsequently identified as galectin-9 (gal-9) [14], a b-galactoside binding lectin that belongs to a growing family of animal lectins, the...

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“…These data were in agreement with other publications addressing the distribution of Treg cells in NOD mice. 39 In the thymus, the FACS data showed no difference in the Foxp3-positive cell numbers in NOD versus B10 control mice, while the qRT-PCR data demonstrated a significant decrease of Foxp3 transcripts in NOD mice. These results suggest that the expression of the Foxp3 gene was downregulated in Treg cells in the thymus of NOD mice, while the numbers of these cells remained comparable to that in the control animals.…”

Section: Treg Cells In Plns In T1dmentioning

confidence: 85%

Treg cells in pancreatic lymph nodes: the possible role in diabetogenesis and β cell regeneration in a T1D model

et al. 2012

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Previously, we established a model in which physiologically adequate function of the autologous b cells was recovered in non-obese diabetic (NOD) mice after the onset of hyperglycemia by rendering them hemopoietic chimera. These mice were termed antea-diabetic. In the current study, we addressed the role of T regulatory (Treg) cells in the mechanisms mediating the restoration of euglycemia in the antea-diabetic NOD model. The data generated in this study demonstrated that the numbers of Treg cells were decreased in unmanipulated NOD mice, with the most profound deficiency detected in the pancreatic lymph nodes (PLNs). The impaired retention of the Treg cells in the PLNs correlated with the locally compromised profile of the chemokines involved in their trafficking, with the most prominent decrease observed in SDF-1. The amelioration of autoimmunity and restoration of euglycemia observed in the antea-diabetic mice was associated with restoration of the Treg cell population in the PLNs. These data indicate that the function of the SDF-1/CXCR4 axis and the retention of Treg cells in the PLNs have a potential role in diabetogenesis and in the amelioration of autoimmunity and b cell regeneration in the antea-diabetic model. We have demonstrated in the antea-diabetic mouse model that lifelong recovery of the b cells has a strong correlation with normalization of the Treg cell population in the PLNs. This finding offers new opportunities for testing the immunomodulatory regimens that promote accumulation of Treg cells in the PLNs as a therapeutic approach for type 1 diabetes (T1D).

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Dynamics of Pathogenic and Suppressor T Cells in Autoimmune Diabetes Development

Cited by 219 publications

References 53 publications

Resistance to CD4+CD25+ Regulatory T Cells and TGF-β in Cbl-b−/− Mice

Resistance to CD4+CD25+ Regulatory T Cells and TGF-β in Cbl-b−/− Mice

Attenuation of Th1 response through galectin‐9 and T‐cell Ig mucin 3 interaction inhibits autoimmune diabetes in NOD mice

Treg cells in pancreatic lymph nodes: the possible role in diabetogenesis and β cell regeneration in a T1D model

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