Autoreactive T Follicular Helper Cells Drive Induction of Bullous Pemphigoid-Like Skin Disease.

T follicular helper (Tfh) cells were recently described as a key cell population for the induction of antibody responses, suggesting their crucial role in bullous pemphigoid pathophysiology. However, functional evidence is missing. In this study, we demonstrate that regulatory T cell-deficient scurfy mice, which spontaneously develop skin disease, including human bullous pemphigoid-like characteristics, show highly increased Tfh cell frequencies. After transferring purified autoreactive scurfy Tfh cells into T cell-lacking nude mice, these recipients developed class-switched autoantibodies. Intriguingly, transfer of scurfy Tfh cells resulted in severe erythema and scaling of the skin in recipients, whereas transfer of Tfh cell-depleted scurfy or wild-type CD4+ T cells did not trigger skin disease. Notably, skin disease after scurfy Tfh cell transfer was accompanied by the formation of antibasement membrane autoantibodies and linear C4 complement deposition at the basement membrane in lesional skin. A refined characterization revealed autoantibody reactivity against the bullous pemphigoid antigen BP230, primarily its N-terminal and mid domain in most nude recipients. These findings show a direct pathogenic effect of Tfh cells in inducing skin disease and confirm the crucial role of autoreactive Tfh cells in the induction of antibodies against human bullous pemphigoid autoantigens.