Pemphigus vulgaris (PV) is considered as a model for an autoantibody-mediated organ-specific autoimmune disorder. IgG autoantibodies directed against the desmosomal cadherin desmoglein 3 (Dsg3), the major autoantigen in PV, cause loss of epidermal keratinocyte adhesion, resulting in blisters and erosions of the skin and mucous membranes. The association of human autoimmune diseases with distinct HLA alleles is a well-known phenomenon, such as the association with HLA-DRB1* 04: 02 in PV. However, direct evidence that HLA-DRB1* 04: 02–restricted autoreactive CD4+ T cells recognizing immunodominant epitopes of Dsg3 initiate the production of Dsg3-reactive IgG autoantibodies is still missing. In this study, we show in a humanized HLA-DRB1* 04: 02–transgenic mouse model that HLA-DRB1* 04: 02–restricted T cell recognition of human Dsg3 epitopes leads to the induction of pathogenic IgG Abs that induce loss of epidermal adhesion, a hallmark in the immune pathogenesis of PV. Activation of Dsg3-reactive CD4+ T cells by distinct human Dsg3 peptides that bind to HLA-DRβ1* 04: 02 is tightly regulated by the HLA-DRB1* 04: 02 allele and leads, via CD40-CD40L–dependent T cell–B cell interaction, to the production of IgG Abs that recognize both N-and COOH-terminal epitopes of the human Dsg3 ectodomain. These findings demonstrate key cellular and humoral immune events in the autoimmune cascade of PV in a humanized HLA-transgenic mouse model. We show that CD4+ T cells recognizing immunodominant Dsg3 epitopes in the context of the PV-associated HLA-DRB1* 04: 02 induce the secretion of Dsg3-specific IgG in vivo. Finally, these results identify Dsg3-reactive CD4+ T cells as potential therapeutic targets in the future.