Inhibition of the Transcription Factor Foxp3 Converts Desmoglein 3-Specific Type 1 Regulatory T Cells into Th2-Like Cells

Veldman, Christian; Pahl, Andreas; Beissert, Stefan; Hansen, Wiebke; Buer, Jan; Dieckmann, Detlef; Schuler, Gerold; Hertl, Michael

doi:10.4049/jimmunol.176.5.3215

Cited by 59 publications

(55 citation statements)

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“…In contrast, it has been recently reported that human Tr1 cell clones specific for desmoglein3, the dominant autoantigen in pemphigus vulgaris, constitutively express FOXP3 [31]. Interestingly, silencing of FOXP3 expression resulted in a shift from Tr1 towards a Th2-like phenotype and the loss of the ability to suppress Teff cells in vitro [31]. The reason for these controversial results on the role of FOXP3 expression in Tr1 cell suppressor function in vitro remains to be elucidated.…”

Section: Foxp3 and Adaptive T Regulatory Type 1 (Tr1) Cellsmentioning

confidence: 97%

“…Functional suppressor Tr1 cells can be differentiated in vitro from naive T cells of IPEX patients lacking FOXP3 [30], demonstrating that Tr1 cells do not require FOXP3 to mediate their suppressor activity. In contrast, it has been recently reported that human Tr1 cell clones specific for desmoglein3, the dominant autoantigen in pemphigus vulgaris, constitutively express FOXP3 [31]. Interestingly, silencing of FOXP3 expression resulted in a shift from Tr1 towards a Th2-like phenotype and the loss of the ability to suppress Teff cells in vitro [31].…”

Section: Foxp3 and Adaptive T Regulatory Type 1 (Tr1) Cellsmentioning

confidence: 97%

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Is FOXP3 a bona fide marker for human regulatory T cells?

2008

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FOXP3 is a specific marker for naturally occurring regulatory T cells (nTreg). FOXP3 expression is correlated with development and function of nTreg. Recent evidence suggests that, upon activation, human effector T (Teff) cells and type 1 regulatory T (Tr1) cells can express FOXP3, albeit transiently. While the role of transient FOXP3 expression in Teff cells is poorly understood, it is becoming clear that it does not correlate with suppressor function. Furthermore, FOXP3‐independent mechanisms, mediated by IL‐10, contribute to the induction and suppressor functions of Tr1 cells. See accompanying commentary:

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Section: Foxp3 and Adaptive T Regulatory Type 1 (Tr1) Cellsmentioning

confidence: 97%

Section: Foxp3 and Adaptive T Regulatory Type 1 (Tr1) Cellsmentioning

confidence: 97%

Is FOXP3 a bona fide marker for human regulatory T cells?

2008

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“…ture of human Tr1s specific for Dsg3 (56). These Dsg3-specific Tr1s expressed phenotypic markers of Tregs such as cytotoxic T cell antigen-4, glucocorticoid-induced TNF receptor, and membrane-bound TGF-β and inhibited the activation of autoreactive Th1 and Th2 cells via the secretion of IL-10 and TGF-β ( Figure 5).…”

Section: Figurementioning

confidence: 99%

T cell control in autoimmune bullous skin disorders

Hertl¹

2006

Journal of Clinical Investigation

198

129

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Autoimmune bullous disorders are a group of severe skin diseases characterized clinically by blisters and erosions of skin and/or mucous membranes. A hallmark of these disorders is the presence of IgG and occasionally IgA autoantibodies that target distinct adhesion structures of the epidermis, dermoepidermal basement membrane, and anchoring fibrils of the dermis. This Review focuses on the potential role of autoreactive T cells in the pathogenesis of these disorders. Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are the best-characterized bullous disorders with regard to pathogenesis and T cell involvement. Activation of autoreactive T cells in PV and BP is restricted by distinct HLA class II alleles that are prevalent in individuals with these disorders. Autoreactive T cells are not only present in patients but can also be detected in healthy individuals. Recently, a subset of autoreactive T cells with remarkable regulatory function was identified in healthy individuals and to a much lesser extent in patients with PV, suggesting that the occurrence of autoimmune bullous disorders may be linked to a dysfunction of Tregs.Autoimmune bullous skin disorders are characterized by the presence of autoantibodies that target distinct adhesion molecules of the epidermis and dermoepidermal basement membrane zone, leading to a loss of adhesive function of the target antigen(s) and, clinically, to the appearance of blisters and erosions (1, 2) (Figures 1 and 2). Desmogleins are transmembranous components of desmosomes, adhesion units specialized in conferring epidermal keratinocyte cohesion and linked to intercellular molecules of the desmosomal plaque, which in turn interact with components of the cytoskeleton (Figure 1). In pemphigus, IgG autoantibodies against desmoglein 3 (Dsg3) and Dsg1 lead to loss of desmosomal adhesion of epidermal keratinocytes and intraepidermal blister formation (Figure 2). In the pemphigoids, IgG autoantibodies against components of the dermoepidermal basement membrane such as bullous pemphigoid (BP) antigen 180 (BP180; also referred to as BP antigen 2 and type XVII collagen), BP antigen 230 (BP230; also referred to as BP antigen 1), and laminin 5 interfere with the adhesion of basal epidermal keratinocytes to the dermoepidermal basement membrane zone (Figure 1). BP180 and BP230 are transmembranous and intracellular components, respectively, of hemidesmosomes of basal epidermal keratinocytes, while laminin 5 is a ligand of BP180 located in the lamina lucida of the basement membrane zone (Figure 1). The autoantigen of epidermolysis bullosa, type VII collagen, is the major component of anchoring fibrils that connect the dermoepidermal basement membrane with interstitial collagen bundles of the dermis (Figure 1). The autoantigen of dermatitis herpetiformis, epidermal transglutaminase, is targeted by autoantibodies of the IgA class in the papillary dermis (Figure 2).Based on the specificity of the targeted antigens, several clinically and immune serologically distinct bullous disorders have be...

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“…Clinically, a deficiency in Treg function or decrease in the proportion of Treg has been observed to influence the pathogenesis of collagen or autoimmune diseases such as multiple sclerosis (9), rheumatoid arthritis (10), systemic lupus erythematosus (II), and pemphigus vulgaris (12). These findings at the cellular and molecular levels provide firm evidence that CD4+CD25+FoxpY regulatory T cells are an indispensable cellular constituent of the normal immune system, and that these cells play crucial roles in establishing and maintaining immunologic self-tolerance and immune homeostasis.…”

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confidence: 99%

Reductive Alteration of the Regulatory Function of the CD4+CD25+ T Cell Fraction in Silicosis Patients

Hayashi

Miura

Maeda

et al. 2010

Int J Immunopathol Pharmacol

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Causal links have been documented between silica and rheumatoid arthritis, lupus erythematosus, systemic sclerosis and glomerulonephritis. Two different effects of silica have been suggested, an enhanced inflammatory response in the pulmonary region (e.g. activation of alveolar macrophages) and dysregulation of autoimmunity. Based on our previous reports showing in vitro activation of peripheral T cells by silica and reduced regulatory function of the peripheral CD4+CD25+ fraction in which FoxP3+ regulatory T cells (Treg) are located, reconstitution of the CD4+CD25+ fraction in silicosis patients (SILs) was investigated. Since T cells in peripheral CD4+CD25+ and CD4+CD25− (effector T cells; Teff) fractions from SILs showed higher expression of pd-1 (a marker gene for T cell activation) in comparison to that of healthy donors (HDs), chronic T cell activation was considered to have occurred in SILs. In this study, a higher expression of the CD95/Fas molecule in Treg was recorded from silicosis patients (SILs) compared to healthy donors (HDs), and excess loss of FoxP3+ Treg in freshly isolated peripheral blood mononuclear cells (PBMCs) from SILs relative to HDs was demonstrated when these cells were cultured with silica ex vivo, whereas CD25+ cells were not reduced due to contamination of activated Teff in the CD4+CD25+ fraction. The activation of both Teff and Treg results in reconstitution of the peripheral CD4+ CD25+ fraction, loss of Treg and contamination of activated Teff, resulting in reduction of the number and function of Treg. These results contribute to our understanding of the development of autoimmune diseases found in SILs.

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Inhibition of the Transcription Factor Foxp3 Converts Desmoglein 3-Specific Type 1 Regulatory T Cells into Th2-Like Cells

Cited by 59 publications

References 54 publications

Is FOXP3 a bona fide marker for human regulatory T cells?

Is FOXP3 a bona fide marker for human regulatory T cells?

T cell control in autoimmune bullous skin disorders

Reductive Alteration of the Regulatory Function of the CD4+CD25+ T Cell Fraction in Silicosis Patients

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