The CD4+CD25+Foxp3+ regulatory T cells (Tregs) play suppressive roles in various types of autoimmunity. It has been reported that Tregs develop in the thymus after high-affinity interaction of their TCR with self-peptide/MHC ligands mostly utilizing TCR-transgenic system. In this study, we examined whether the specific antigen is involved in the development of polyclonal Tregs in pemphigus vulgaris (PV), an autoimmune blistering disease caused by anti-desmoglein 3 (Dsg3) IgG antibodies, as a model system. Adoptive transfer of splenocytes of Dsg3-/- mice immunized with recombinant mouse Dsg3 to Rag2-/- recipient mice expressing Dsg3 resulted in the stable production of anti-Dsg3 IgG and the development of PV phenotypes. We show here that Tregs control anti-Dsg3 antibody production in PV model mice: the adoptive transfer of Tregs and the depletion of endogenous Tregs suppressed and augmented, respectively, the anti-Dsg3 antibody production. To examine whether the endogenous expression of Dsg3 is involved in the generation of these PV-relevant Tregs, we compared the potential of wild-type Tregs with that of Tregs from Dsg3. -/- mice. Polyclonal Tregs from Dsg3-/- mice were more potent than that of wild-type mice, in both adoptive transfer and Treg-depletion experiments, while suppressive activities against IgG production against an irrelevant antigen were similar between Tregs from wild-type and Dsg3-/- mice. Our observation implies that Tregs capable of suppressing Th cells that drive autoantibody production can develop in the absence of the target antigen.
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