IFNG-producing self-reactive CD4+ T cells drive autoimmune adrenalitis in a mouse model of Addison's disease

Autoimmune Addisons disease (AD) is a rare, life-threatening endocrine disorder caused by immune-mediated destruction of the adrenal cortex. AD frequently occurs in patients with autoimmune polyglandular syndrome type 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 established a mouse model of Experimental Autoimmune Adrenalitis by targeting the adrenal self-antigen CYP11A1. Immunization with CYP11A1-derived peptides elicited clonal expansion of CYP11A1-specific T-cell clones and the adrenal infiltration of CD4+ and CD8+ T cells and myeloid cells. Inflammation progressed to granulomatous lesions and culminated in adrenal insufficiency in AIRE-deficient mice with impaired central tolerance. A modification of the model based an adoptive transfer of polyclonal CYP11A1-stimulated CD4+ T cells into T-cell deficient hosts accelerated adrenal dysfunction. In contrast, IFNG-deficient CD4+ T cells induced only mild granulomatous inflammation and failed to cause overt adrenal insufficiency. These findings established a tractable mouse model for dissecting AD pathogenesis and identified CD4+ T cell-derived IFNG as a key effector of adrenal autoimmunity, providing a preclinical platform for testing targeted immunotherapies.