IFN-γ-driven CD8⁺ T-cell-keratinocyte cross talk underlies inflammation and blistering in pemphigus lesions.

Abstract

Pemphigus is an autoimmune bullous disease primarily driven by anti-desmoglein (Dsg) autoantibodies. However, the disease pathogenesis beyond anti-Dsg autoantibodies remains unclear. We sought to explore the pathogenic role of IFN-γ in pemphigus and to evaluate the therapeutic potential of targeting the IFN-γ-JAK pathway. The pathogenetic effects of IFN-γ signaling in pemphigus were investigated by integrated single cell analysis, ex vivo human skin explants, and cocultures. Therapeutic efficacy of the JAK1 inhibitor abrocitinib was evaluated in a murine pemphigus model and in refractory pemphigus patients. IFN-γ-expressing T cells largely infiltrate pemphigus lesions and drive IFN-γ-dominant inflammation. IFN-γ-activated keratinocytes secrete C-X-C motif chemokines CXCL9/10/11 to recruit more CD8⁺ T cells. Notably, IFN-γ primes keratinocytes to become more susceptible to CD8⁺ T-cell-mediated cytotoxicity. Moreover, IFN-γ synergizes with anti-Dsg autoantibodies to induce keratinocyte dissociation through p38 activation and augments anti-Dsg autoantibody production. Oral JAK1 inhibitor abrocitinib effectively attenuated IFN-γ-dominant inflammation and improved skin lesions in a murine pemphigus model and in patients with refractory disease. A self-amplifying inflammatory circuit between IFN-γ⁺CD8⁺ T cells and keratinocytes acts as a key driver of pemphigus pathogenesis and provides a mechanistic rationale for targeting the IFN-γ-JAK pathway in its treatment.