Abstract:  Pemphigus foliaceus (PF) is a severe autoimmune bullous disorder, characterized by autoantibodies (autoAb) against desmoglein 1 (Dsg1). As T cells may be critical in the pathology of PF, the aim of the present study was to identify and characterize autoaggressive T‐helper cells reactive to Dsg1 in PF patients and healthy individuals. Eight patients with the clinical diagnosis of PF and six HLA class II‐matched healthy individuals were examined. By magnetic cell‐sorting (MACS) cytokine‐secretion assay, Dsg1‐responsive T‐helper (Th) 1 and Th2 cells were isolated and cloned by limiting dilution. The generated T‐cell clones (TCC) were characterized regarding proliferative response, TCR Vβ‐chain usage, and cytokine profile upon in vitro stimulation with Dsg1. Both Dsg1‐reactive Th1 and Th2 cells were detected in PF patients and controls at similar frequencies. A total of 15 Th1 and Th2 clones were isolated from patients and 27 TCC from healthy controls. Analysis of TCR Vβ‐chain usage of autoreactive T cells from both groups revealed no predominance of a specific Vβ chain. Noteworthy, the isolated TCC showed a polarized Th1‐ or Th2‐like phenotype upon in vitro culture and stable expression of Th1 or Th2 cytokines during long‐term in vitro culture. In summary, our data demonstrate that T‐cell autoreactivity against Dsg1 is not restricted to patients with PF. Moreover, both Th1 and Th2 cells were present in patients and healthy donors, suggesting that the loss of B‐cell tolerance against Dsg1 in PF is not exclusively determined by the presence of autoaggressive T cells.