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Inhibition of the Transcription Factor Foxp3 Converts Desmoglein 3-Specific Type 1 Regulatory T Cells into Th2-Like Cells¹

Christian Veldman^2,*,, Andreas Pahl, Stefan Beissert, Wiebke Hansen^¶, Jan Buer^¶, Detlef Dieckmann^*, Gerold Schuler^* and Michael Hertl^*,

^* Department of Dermatology, University of Erlangen-Nürnberg, Erlangen, Germany; University of Marburg, Marburg, Germany; Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, Erlangen, Germany; Department of Dermatology, University of Münster, Münster, Germany; and ^¶ Department of Mucosal Immunity, German Research Centre for Biotechnology, Braunschweig, Germany

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-, 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.