Background Alopecia areata (AA) is a T‐cell mediated putative autoimmune disease of hair follicles, which can be transferred by CD4+ T cells. However, whether T‐helper (Th) 1 or Th2 cytokines are predominant has not yet been defined.

Objectives To elucidate the importance of Th1 cells in the pathogenesis of AA we investigated the functional role of interferon (IFN)‐γ in the experimental induction of AA.

Methods AA was experimentally induced by grafting full‐thickness skin from AA‐affected C3H/HeJ mice on to C3H/HeJ mice with a targeted deletion of the Th1 cytokine IFN‐γ gene (IFNγ^−/−) and on to wild‐type mice (IFNγ^+/+).

Results While 90% of wild‐type mice developed AA, none of the IFNγ^−/− mice exhibited hair loss. Immunohistochemistry of skin sections revealed a dense perifollicular and intrafollicular infiltrate of CD4+ and CD8+ T cells in controls, while in IFNγ^−/− mice skin‐infiltrating CD8+ T cells were absent and the number of CD4+ cells was significantly reduced. Aberrant expression of major histocompatibility complex class I and II molecules in the putative immune‐privileged infrainfundibular site of the hair follicle was found to be weaker in AA‐resistant IFNγ^−/− mice than in control mice with AA. Flow cytometry revealed that leucocytes of IFNγ^−/− mice did not respond to the transfer of AA‐affected skin. As distinct from IFNγ^+/+ mice, neither T‐cell activation markers nor Th1 cytokines were upregulated in draining lymph node cells or skin‐infiltrating leucocytes of AA‐resistant IFNγ^−/− mice. However, there was no evidence for a shift towards a Th2 cytokine profile, nor for upregulation of regulatory T cells in IFNγ^−/− mice.

Conclusions IFNγ^−/− mice fail to activate Th1 cells in response to the transplanted (auto)antigens, which suggests an essential requirement for IFN‐γ‐mediated Th1 activation in the induction of AA.