TGF-β1 Alters APC Preference, Polarizing Islet Antigen Responses toward a Th2 Phenotype

King, Charles M.; Davies, Joanna D.; Mueller, Régula; Lee, Myung-Shik; Krahl, Troy; Yeung, Brian; O'Connor, Eric; Sarvetnick, Nora

doi:10.1016/s1074-7613(00)80565-8

Cited by 176 publications

(119 citation statements)

References 43 publications

(12 reference statements)

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“…The development of diabetes in NOD mice occurs as a result of the early development of lymphoid cell infiltration around the islets at 3 weeks of age and a late event wherein beta-cell destruction occurs several months later, suggesting that the antiislet immune response is countered by regulatory mechanisms (24). Protection conferred by constitutive expression of TGF-␤ was previously reported (21,25), but constitutive expression of TGF-␤ in the islets led to fibrosis that compromised investigations of the mechanisms underlying immune suppression. To overcome this limitation, we generated mice in which TGF-␤ expression can be induced temporally by the tetracycline regulatory system (Fig.…”

Section: Transient Expression Of Tgf-␤ In the Islets Is Sufficient Tomentioning

confidence: 92%

“…Next we considered suppression of T helper (Th) 1 function through immune deviation toward a Th2 profile as previously reported from mouse models of constitutive expression of TGF-␤ in NOD mice (25). In these mice, TGF-␤ modified the profile of antigens presented by antigen-presenting cells and caused betacell-specific splenic T cells to shift from IFN-␥-producing Th1 cells to IL-4-secreting Th2 cells.…”

Section: Transient Expression Of Tgf-␤ In the Islets Is Sufficient Tomentioning

confidence: 99%

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TGF-β regulatesin vivoexpansion of Foxp3-expressing CD4⁺CD25⁺regulatory T cells responsible for protection against diabetes

Peng

Laouar

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

381

273

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CD4 ؉ CD25 ؉ regulatory T cells are essential in the protection from organ-specific autoimmune diseases. In the pancreas, they inhibit actions of autoreactive T cells and thereby prevent diabetes progression. The signals that control the generation, the maintenance, or the expansion of regulatory T cell pool in vivo remain poorly understood. Here we show that a transient pulse of transforming growth factor ␤ (TGF-␤) in the islets during the priming phase of diabetes is sufficient to inhibit disease onset by promoting the expansion of intraislet CD4 ؉ CD25 ؉ T cell pool. Approximately 40 -50% of intraislet CD4 ؉ T cells expressed the CD25 marker and exhibited characteristics of regulatory T cells including small size, high level of intracellular CTLA-4, expression of Foxp3, and transfer of protection against diabetes. Results from in vivo incorporation of BrdUrd revealed that the generation of a high frequency of regulatory T cells in the islets is due to in situ expansion upon TGF-␤ expression. Thus, these findings demonstrate a previously uncharacterized mechanism by which TGF-␤ inhibits autoimmune diseases via regulation of the size of the CD4 ؉ CD25 ؉ regulatory T cell pool in vivo.T ype I diabetes is an autoimmune disease that results from the failure of tolerance to beta-cell antigens (1). The mechanisms that have evolved to ensure discrimination between self and nonself are highly complex and not foolproof. Models of passive tolerance, such as thymic deletion of autoreactive T cells or nonreponsiveness in the periphery because of anergy or ignorance, cannot account for the presence of autoreactive T cells in healthy individuals despite the absence of the development of organ-specific autoimmune diseases. T cells endowed with suppressive function to control actions of autoreactive T cells were described decades ago and were thought originally to be a specialized T cell population the effect of which would be mediated by secreted antigen-specific factors (2). Nowadays, suppressor T cells (also referred to as regulatory T cells) are delineated into two cell subsets of natural regulatory (CD4 ϩ CD25 ϩ ) cells that emerge from the thymus (3, 4) and adaptive regulatory (CD4 ϩ CD25 Ϫ ) cells induced in the periphery to develop suppressive activity (5-7). However, this concept of dichotomous thymic CD25 ϩ versus adaptive CD25 Ϫ regulatory T cells has been challenged by several reports, supporting evidence for the peripheral generation of CD25 ϩ regulatory T cells in vivo and in vitro (8)(9)(10)(11)(12). The finding that suppressive functions are instructively programmed by the expression of Foxp3 finally provided the basis for integrating a unified model of regulatory T cell diversity (13-15). Forced expression of Foxp3 in CD4 ϩ CD25 Ϫ nonregulatory T cells, either by retroviral expression or in transgenic mice, showed acquisition of suppressive activity in vitro and inhibition of disease in vivo, inducing in a substantial proportion of Foxp3-bearing cells the expression of CD25 and GITR markers indicating that ex...

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Section: Transient Expression Of Tgf-␤ In the Islets Is Sufficient Tomentioning

confidence: 92%

Section: Transient Expression Of Tgf-␤ In the Islets Is Sufficient Tomentioning

confidence: 99%

TGF-β regulatesin vivoexpansion of Foxp3-expressing CD4⁺CD25⁺regulatory T cells responsible for protection against diabetes

Peng

Laouar

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

381

273

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“…Multiple models of pancreas-specific overexpression of active TGF-b show that TGF-b inhibits diabetes development (King et al 1998;Moritani et al 1998;Grewal et al 2002). Protection against T1D is associated with the induction of tolerogenic T-cell responses, suggesting that TGF-b regulates diabetogenic T cells to prevent disease (King et al 1998;Moritani et al 1998).…”

Section: Diabetesmentioning

confidence: 99%

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

Sanjabi

2017

Cold Spring Harb Perspect Biol

421

306

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Transforming growth factor b (TGF-b) is a pleiotropic cytokine involved in both suppressive and inflammatory immune responses. After 30 years of intense study, we have only begun to elucidate how TGF-b alters immunity under various conditions. Under steady-state conditions, TGF-b regulates thymic T-cell selection and maintains homeostasis of the naïve T-cell pool. TGF-b inhibits cytotoxic T lymphocyte (CTL), Th1-, and Th2-cell differentiation while promoting peripheral ( p)Treg-, Th17-, Th9-, and Tfh-cell generation, and T-cell tissue residence in response to immune challenges. Similarly, TGF-b controls the proliferation, survival, activation, and differentiation of B cells, as well as the development and functions of innate cells, including natural killer (NK) cells, macrophages, dendritic cells, and granulocytes. Collectively, TGF-b plays a pivotal role in maintaining peripheral tolerance against self-and innocuous antigens, such as food, commensal bacteria, and fetal alloantigens, and in controlling immune responses to pathogens.

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“…TGF-b1, expressed transgenically in pancreatic islet beta cells, protected NOD mice from diabetes [22]. In other studies, transgenic expression of TGF-b1 in pancreatic islet alpha cells protected NOD mice from diabetes, and the protective action of TGF-b1 was related to blocking the cytotoxic effects of diabetogenic effector lymphocytes [23].…”

Section: Discussionmentioning

confidence: 84%

Combination therapy with low dose sirolimus and tacrolimus is synergistic in preventing spontaneous and recurrent autoimmune diabetes in non-obese diabetic mice

et al. 2002

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Type I (insulin-dependent) diabetes mellitus is the result of the selective destruction of pancreatic islet beta cells by an autoimmune process. A variety of procedures and therapies that delete, suppress or modulate functions of immune system cells can block the autoimmune response against islet beta cells and prevent beta-cell destruction and Type I diabetes. Immunotherapy might even reverse established diabetes in the NOD mouse, a model of human Type I diabetes [1,2]. In human Type I diabetes, there is also more potential for the restoration of endogenous insulin secretion and reversal of diabetes than has been assumed. For example, patients receiving the immunosuppressive drug cyclosporine experienced more frequent and longer duration remissions than Diabetologia (2002) Abstract Aims/hypothesis. Sirolimus and tacrolimus are immunosuppressive drugs that prevent rejection of pancreatic islet allografts transplanted into patients with Type I (insulin-dependent) diabetes mellitus. This study aimed to determine whether sirolimus and tacrolimus can prevent autoimmune beta-cell destruction, and if so, what the mechanisms of action are. Methods. Sirolimus and tacrolimus were given separately and together to female non-obese diabetic (NOD) mice from age 12 to 35 weeks. Diabetes incidence was determined and pancreatic insulitis and insulin content were measured. Sirolimus and tacrolimus were also given separately and together to diabetic NOD mice from the time of syngeneic islet transplantation until the reappearance of hyperglycaemia. Islet grafts were examined by RT-PCR assay for expression of interferon (IFN)-g, interleukin (IL)-2, IL-4, IL-10 and transforming growth factor (TGF)-b1. Results. Low doses of sirolimus (0.1 mg/kg) and tacrolimus (0.1 mg/kg) were synergistic in reducing insulitis, preserving pancreatic insulin content and preventing diabetes in female NOD mice (8 % diabetes incidence at 35 weeks vs 66 % in vehicle-treated mice). Also, the combination of sirolimus and tacrolimus prolonged syngeneic islet graft survival (median 34 days vs 13 days for vehicle-treated mice). Islet grafts from sirolimus plus tacrolimus-treated mice expressed significantly decreased mRNA contents of Th1-type cytokines (IFN-g and IL-2) and the highest ratio of TGF-b1/IFN-g mRNA. Conclusion/interpretation. These findings suggest that combination therapy with sirolimus and tacrolimus prevent autoimmune beta-cell destruction by upregulating expression of the immunoregulatory cytokine, TGF-b1 and reducing Th1 cytokines (IFN-g and IL-2) expressed in the islets. Low-dose sirolimus and tacrolimus combination therapy could warrant consideration for prevention or early treatment of human Type I diabetes. [Diabetologia (2002) 45: 224±230]

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TGF-β1 Alters APC Preference, Polarizing Islet Antigen Responses toward a Th2 Phenotype

Cited by 176 publications

References 43 publications

TGF-β regulatesin vivoexpansion of Foxp3-expressing CD4⁺CD25⁺regulatory T cells responsible for protection against diabetes

TGF-β regulatesin vivoexpansion of Foxp3-expressing CD4⁺CD25⁺regulatory T cells responsible for protection against diabetes

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

Combination therapy with low dose sirolimus and tacrolimus is synergistic in preventing spontaneous and recurrent autoimmune diabetes in non-obese diabetic mice

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TGF-β1 Alters APC Preference, Polarizing Islet Antigen Responses toward a Th2 Phenotype

Cited by 176 publications

References 43 publications

TGF-β regulatesin vivoexpansion of Foxp3-expressing CD4+CD25+regulatory T cells responsible for protection against diabetes

TGF-β regulatesin vivoexpansion of Foxp3-expressing CD4+CD25+regulatory T cells responsible for protection against diabetes

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

Combination therapy with low dose sirolimus and tacrolimus is synergistic in preventing spontaneous and recurrent autoimmune diabetes in non-obese diabetic mice

Contact Info

Product

Resources

About

TGF-β regulatesin vivoexpansion of Foxp3-expressing CD4⁺CD25⁺regulatory T cells responsible for protection against diabetes

TGF-β regulatesin vivoexpansion of Foxp3-expressing CD4⁺CD25⁺regulatory T cells responsible for protection against diabetes