Immune signatures associated with human adrenocortical hypertension

Background: The finding of autoantibodies against the angiotensin II type-1 receptor (AT1R) in human primary aldosteronism (PA) suggests a loss of immunological tolerance; however, whether autoreactive AT1R-specific T cells exist and if and how aldosterone or cortisol modulate their activity is unknown. Methods: Peripheral blood mononuclear cells from patients with confirmed PA and healthy donors were stimulated with overlapping AT1R peptides to identify autoreactive T cells. The chronic and rapid aldosterone effects on CD4+ and CD8+ T cells and the receptors involved were evaluated using mineralocorticoid receptor (MR) and G-protein estrogen receptor (GPER) antagonists. Cortisol effects and 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) expression were also examined. Functional cytotoxicity of AT1R-specific CD8+ clones toward human endothelial cells was assessed. Results: Compared to healthy donors, PA patients exhibited a marked expansion of AT1R-specific CD8+ T cells recognizing the AFHYESQ epitope of the second extracellular AT1R loop, which was not detected in CD4+ cells. Both T-cell subsets expressed MR and GPER but lacked 11βHSD2 expression. Chronic aldosterone exposure enhanced CD8+ proliferation and IFN-γ production through MR. Rapid aldosterone stimulation activated CD8+ cells via MR and GPER. In CD8+ cells cortisol also increased IFN-γ-production through MR. AT1R-specific CD8+ T-cell clones induced apoptosis of human endothelial cells expressing AT1R. Conclusions: PA patients harbor autoreactive AT1R-specific CD8+ T cells that respond to aldosterone and cortisol through MR and GPER. These findings identify an adaptive autoimmune mechanism in PA and provide insight into how steroid-driven T-cell activation may contribute to hypertension-mediated organ damage in aldosteronism and hypercortisolism.