Dsg3- and Dsg1-reactive Th1 and Th2 cells are present in patients with PV and healthy carriers of PV-associated HLA class II alleles, which recognize identical epitopes of the Dsg3 ectodomain presented by APCs such as dendritic cells and B cells. There is a predominance of Dsg3-reactive Th2 cells in PV and of autoreactive Th1 cells in healthy individuals. In addition, Tr1s specific for Dsg3 are present at higher frequencies in healthy individuals than in PV patients. These Tr1s express the phenotypic markers glucocorticoid-induced TNF receptor (GITR), membrane-bound TGF-β (mTGF-β), and cytotoxic T cell antigen–4 (CTLA-4) and inhibit the activation of Dsg3-specific autoreactive Th1 and Th2 cells via the secretion of IL-10 and TGF-β and the uptake of exogenous IL-2 produced by the Th cells. Inactivation of the regulatory transcription factor Foxp3 by antisense deoxynucleotides converts Tr1s into a Th2-like population with regard to cytokine profile, loss of inhibitory function on Th cells, and the ability to develop a proliferative response to Dsg3. Thus an imbalance of the putative relationship between autoreactive Th and Tr1 cells may be critical in the pathogenesis of PV. Hence Dsg-specific Tr1s may be critical for the maintenance of tolerance against Dsg3 and Dsg1 in health and the restoration of tolerance against these autoantigens in remittent PV.