Pemphigus vulgaris (PV) is a Th2-dominant autoimmune skin disease. We showed that indeed active PV patients had a biased Th2 response and specific IgG4 autoantibodies were dominant. To further investigate the role of antigen-specific Th2 cells in the regulation of pathogenic Dsg3-IgG antibody production, we used recombined Dsg3 protein to immunize wildtype C57BL/6 mice with aluminum hydroxide or complete Freund's adjuvant as adjuvant. CD4 T cells from Dsg3-immunized mice were adoptively transferred into TCR-β chain deficient mice. The transferred CD4 T cells were readily seen in the peripheral blood and spleen, and interacted with B cells, resulting in B-cell activation. Furthermore, transferred CD4 T cells from mice immunized with Dsg3 plus Alum with Th2 phenotype were able to render unprimed B cells to secrete Dsg3-specific IgG1 antibody in vivo. Taken together, these results provide the first demonstration of direct role of Dsg3-reactive CD4 T (Th2) cells in the regulation of pathologic anti-Dsg3 antibody production. © Springer Science+Business Media, LLC 2011.