IFN-γ-producing self-reactive CD4+ T cells induce autoimmune adrenalitis in a mouse model of Addison's disease.

Autoimmune Addison's disease (AD) is a rare but life-threatening disorder caused by immune-mediated destruction of the adrenal cortex, and progress in therapy has been limited by insufficient mechanistic insight. Here, we establish a model of experimental autoimmune adrenalitis that recapitulates key features of AD and reveals sex-dependent differences in disease manifestation within the model. Immunization with peptides derived from the adrenal self-antigen CYP11A1 induces corticosterone insufficiency. We show that autoimmune adrenalitis is driven by IFN-γ produced by self-reactive CD4+ T cells, promoting granulomatous inflammation in the adrenal cortex. Together, these findings identify IFN-γ as a central effector of autoimmune adrenalitis and suggest that targeting the IFN-γ pathway may represent a potential therapeutic strategy for AD.