IFN-γ enhances cell-mediated cytotoxicity against keratinocytes via JAK2/STAT1 in lichen planus.

Identifying keratinocyte killers: Lichen planus is an inflammatory disease characterized by lesions on the skin or mouth. Although there are no approved treatments, T cell infiltration and keratinocyte death are thought to be involved. Shao et al. analyzed samples from patients and used an in vitro coculture system to identify immune pathways involved in this debilitating disease. They discovered that IFN-γ primed keratinocytes to become vulnerable to CD8⁺ cytotoxic T cells. As this axis depends on JAK/STAT signaling, JAK inhibitors already in the clinic for other indications could be used to prevent keratinocyte death, providing relief to patients with lichen planus. Lichen planus (LP) is a chronic debilitating inflammatory disease of unknown etiology affecting the skin, nails, and mucosa with no current FDA-approved treatments. It is histologically characterized by dense infiltration of T cells and epidermal keratinocyte apoptosis. Using global transcriptomic profiling of patient skin samples, we demonstrate that LP is characterized by a type II interferon (IFN) inflammatory response. The type II IFN, IFN-γ, is demonstrated to prime keratinocytes and increase their susceptibility to CD8⁺ T cell–mediated cytotoxic responses through MHC class I induction in a coculture model. We show that this process is dependent on Janus kinase 2 (JAK2) and signal transducer and activator of transcription 1 (STAT1), but not JAK1 or STAT2 signaling. Last, using drug prediction algorithms, we identify JAK inhibitors as promising therapeutic agents in LP and demonstrate that the JAK1/2 inhibitor baricitinib fully protects keratinocytes against cell-mediated cytotoxic responses in vitro. In summary, this work elucidates the role and mechanisms of IFN-γ in LP pathogenesis and provides evidence for the therapeutic use of JAK inhibitors to limit cell-mediated cytotoxicity in patients with LP. [ABSTRACT FROM AUTHOR]