Non‐Th2 Regulatory T‐Cell Control of Th1 Autoimmunity

Bach, Jean‐François

doi:10.1046/j.1365-3083.2001.00945.x

Cited by 45 publications

(26 citation statements)

References 84 publications

(95 reference statements)

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“…63 The IFN-␥ axis can be antagonized by T H 2-type cytokines, especially IL-4, 70 as well as by regulatory cytokines, such as TGF-␤1 or IL-10. 71 As noted above, these cytokines exert some effects directly on T cells, shutting off IFN-␥ secretion, but IL-4 and regulatory cytokines also exert effects on APCs, eg, turning off IL-12 production. The signals which initiate these alternative responses are less clear than those which turn on the IFN-␥ axis; the T H 2 response has sometimes been described as a default pathway.…”

Section: T H 1 Effector Cells and Cd8mentioning

confidence: 96%

Interferon-γ Axis in Graft Arteriosclerosis

Tellides

Pober

2007

Circulation Research

104

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Abstract-Cardiac transplantation is the most effective treatment for advanced heart failure. Despite improvements in immunosuppression therapy that prevent acute rejection, cardiac allografts fail at rates of 3% to 5% per posttransplant year. The hallmark morphological lesion of chronically failing cardiac allografts, also seen in chronic renal and liver graft failure, is luminal stenosis of blood vessels, especially of conduit arteries. Late graft failure results from widespread secondary ischemic injury to the graft parenchyma rather than direct immune-mediated damage. Although this process affects the entire graft vasculature, graft arteriosclerosis is a suitable term to describe the problem because it applies to different types of failing organs and because it emphasizes the central feature, namely an accelerated form of arterial injury and remodeling. The precise pathogenesis of graft arteriosclerosis is unknown. In this review, we make the case that the signature T-helper type 1 cytokine, interferon (IFN)-␥, is a key effector in graft arteriosclerosis, which, together with the IFN-␥-inducing cytokine interleukin-12 and IFN-␥-inducible chemokines such as CXCR3 ligands, constitute a positive feedback loop for T-cell activation, differentiation, and recruitment that we refer to as the IFN-␥ axis. We evaluate the evidence to support this hypothesis in clinical observational and experimental animal studies. Additionally, we examine the regulation of IFN-␥ production within the artery wall, the effects of IFN-␥ on vessel wall cells, and the outcome of therapeutic agents on IFN-␥ production and signaling. These observations lead us to suggest that new therapies for graft arteriosclerosis should be optimized which focus on reducing IFN-␥ synthesis or actions. (Circ Res. 2007;100:622-632.)

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Section: T H 1 Effector Cells and Cd8mentioning

confidence: 96%

Interferon-γ Axis in Graft Arteriosclerosis

Tellides

Pober

2007

Circulation Research

104

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“…Type 1 regulatory (Tr1) T cells mainly exert their suppressive activity through the secretion of IL-10 ( Roncarolo et al, 2001), a potent immunosuppressive cytokine (Moore et al, 2001), while Th3 cells suppress cell activation through TGFβ release (Bach, 2001;Chen et al, 1994). Both in vitro and in vivo studies with recombinant IL-10 and neutralizing antibodies revealed pleiotropic activities of IL-10 on B, T, and mast cells (Moore et al, 2001).…”

Section: B Tr1 Regulatory T Cells and Il-10 Productionmentioning

confidence: 99%

Abnormal Tr1 differentiation in multiple sclerosis

Astier¹,

Hafler²

2007

Journal of Neuroimmunology

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Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). In the recent years, accumulating evidence has supported an immunosuppressive role for regulatory T cells (Tregs). Most studies in the context of autoimmunity have focused on the defects of the CD4 + CD25 high Tregs. However, we recently demonstrated an altered function of Tr1 Treg cells in MS, characterized by a lack of IL-10 secretion. Therefore, several major regulatory T cell defects are involved in human autoimmune disease. Hence, the induction of Tregs or the stimulation of Treg activity may be beneficial for the treatment of such diseases.

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“…Three major classes of immunoregulatory T cells have been described (18): Th2/Th3 cells (19,20), CD4 + CD25 high cells (21,22), and Tr1 cells (23). The immunoregulatory Tr1 cells were identified by Roncarolo and coworkers (24) and secrete IL-10, a potent immunosuppressive cytokine with pleiotropic activities on B, T, and mast cells.…”

Section: Introductionmentioning

confidence: 99%

Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis

Astier¹,

Meiffren²,

Freeman³

et al. 2006

J. Clin. Invest.

258

243

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Loss of Treg function appears to be a critical factor in the pathogenesis of human autoimmune diseases. Attention has focused on defects of CD4 + CD25 high Tregs, and techniques have been developed to determine their function. In contrast, the role of Tr1 regulatory T cells, which secrete the antiinflammatory cytokine IL-10, in autoimmune disease has not been well assessed. CD46 is a newly defined costimulatory molecule for T cell activation, and CD46-costimulated human T cells induce a Tr1 Treg phenotype with considerable amounts of IL-10 secretion. Here, we examined the role of Tr1 cells in patients with multiple sclerosis (MS) by stimulating CD4 + T cells with anti-CD3 and -CD46 mAbs and measuring IL-10 secretion. There were striking defects in the induction of Tr1 cells with CD46 costimulation as measured by IL-10 but not IFN-γ secretion in patients with MS compared with healthy subjects. This loss of Tr1 cell-associated IL-10 secretion was specific to CD46 and not CD28 costimulation and was associated with an altered regulation of the CD46-Cy2 isoform that differentially regulates T cell function in a CD46-transgenic murine model. These data demonstrate a second major Treg defect in human autoimmune disease associated with the CD46 pathway.

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Non‐Th2 Regulatory T‐Cell Control of Th1 Autoimmunity

Cited by 45 publications

References 84 publications

Interferon-γ Axis in Graft Arteriosclerosis

Interferon-γ Axis in Graft Arteriosclerosis

Abnormal Tr1 differentiation in multiple sclerosis

Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis

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