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

Abstract 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 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. Competing Interest Statement The authors have declared no competing interest. Footnotes We changed the format of all Figures, as parts of them were overlayed by automatic bioRxiv text (not visible in the PDF for proofing).