IFNG production by self-reactive CD4 T cells drives the adrenal autoimmune pathology in the mouse model of Addison’s disease

Autoimmune Addison’s disease (AD) is a rare, life-threatening endocrine disorder caused by immune-mediated destruction of the adrenal cortex. AD frequently occurs in patients with APS-1, a monogenic autoimmune syndrome caused by AIRE deficiency. The pathogenesis of AD remains poorly understood due to the lack of suitable animal models. Here, we establish a mouse model of autoimmune adrenalitis by targeting the adrenal self-antigen CYP11A1. Immunization with CYP11A1-derived peptides elicits clonal expansion of CYP11A1-specific clones and the adrenal infiltration of CD4+ and CD8⁺ T cells and myeloid cells. Inflammation progresses to granulomatous lesions and, in Aire-deficient mice, culminates in adrenal insufficiency. A modified model using adoptive transfer of polyclonal, CYP11A1-stimulated CD4⁺ T cells into Rag2- or Cd3e-deficient hosts accelerates adrenal dysfunction and does not require Aire-deficiency. In contrast, IFNG-deficient CD4⁺ T cells induce only mild granulomatous inflammation and fail to cause overt adrenal insufficiency. These findings establish a tractable mouse model for dissecting AD pathogenesis and identify CD4⁺ T cell–derived IFNG as a key effector of adrenal autoimmunity, providing a preclinical platform for testing targeted immunotherapies. The samples from spleen and adrenals of untreated samples and samples treated by CYP11A1 peptide of C57BL6/J mice.