Abstract
Pemphigus vulgaris (PV) is a severe autoimmune bullous skin disorder and is associated with autoantibodies against desmoglein (Dsg)3 that are regulated by Th2 cells. Recently, Dsg3-specific type 1 regulatory T cells (Tr1) were identified that are presumably critical for the maintenance of tolerance against Dsg3 because there is a much lower Dsg3-specific Tr1:Th2 ratio in the PV patients than in healthy individuals. The aim of this study was to down-regulate the transcription factor Foxp3 in Dsg3-specific Tr1 using antisense oligonucleotides because Foxp3 is constitutively expressed by the Dsg3-specific Tr1. Antisense-treated Dsg3-specific Tr1 clones lost expression of Foxp3, glucocorticoid-induced TNFR family-related receptor, and CTLA-4, and started to secrete IL-2, whereas the secretion of IL-5, TGF-beta, and IL-10 remained unchanged. Moreover, antisense treatment induced a proliferative response to Dsg3 of the formerly anergic Tr1 and abrogated their suppressor activity on Dsg3-specific Th2 cell clones. Thus, inhibition of Foxp3 mRNA expression in the Tr1 induced a Th2-like phenotype. In conclusion, Foxp3 expression is inherent to Tr1 function, and modulation of Foxp3 expression in autoaggressive Th2 cells may provide a novel therapeutic approach aimed at restoring tolerance against Dsg3 in PV.
Highlights
ObjectivesThe aim of this study was to down-regulate the transcription factor Foxp in Dsg3-specific Tr1 using antisense oligonucleotides because Foxp is constitutively expressed by the Dsg3-specific Tr1
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Our group identified Dsg3-reactive IL-10-secreting type 1 regulatory T cells (Tr1) in the majority of healthy carriers of Pemphigus vulgaris (PV)-associated HLA class II alleles and in only a few PV patients that suppressed the proliferative response of Dsg3-reactive Th cells in an Ag-specific and cytokine -dependent manner [15]
Summary
The aim of this study was to down-regulate the transcription factor Foxp in Dsg3-specific Tr1 using antisense oligonucleotides because Foxp is constitutively expressed by the Dsg3-specific Tr1
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