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.