PA patients harbor autoreactive AT1R-specific CD8+ T cells that respond to aldosterone and cortisol through MR and GPER, identifying an adaptive autoimmune mechanism in PA that may contribute to hypertension-mediated organ damage in aldosteronism and hypercortisolism.
Key Findings
Results
PA patients exhibited a marked expansion of AT1R-specific CD8+ T cells compared with healthy donors, recognizing the AFHYESQ epitope of the second extracellular AT1R loop.
Peripheral blood mononuclear cells from patients with confirmed PA and healthy donors were stimulated with overlapping AT1R peptides to identify autoreactive T cells.
The AT1R-specific T-cell expansion was detected in CD8+ cells but not in CD4+ cells.
The specific epitope identified was AFHYESQ, located on the second extracellular loop of the AT1R.
Results
Both CD4+ and CD8+ T-cell subsets expressed mineralocorticoid receptor (MR) and G-protein estrogen receptor (GPER) but lacked 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) expression.
MR and GPER expression was confirmed in both T-cell subsets.
The absence of 11βHSD2 expression indicates these cells cannot inactivate cortisol locally, rendering them susceptible to cortisol-driven activation via MR.
These receptors were evaluated using MR and GPER antagonists to assess their functional roles.
Results
Chronic aldosterone exposure enhanced CD8+ T-cell proliferation and IFN-γ production through MR.
The effect was specifically mediated through MR, as determined using an MR antagonist.
Both proliferation and interferon-gamma (IFN-γ) production were enhanced in CD8+ cells under chronic aldosterone exposure.
CD4+ T cells were also evaluated but the proliferation/IFN-γ enhancement under chronic aldosterone was characterized in CD8+ cells.
Results
Rapid aldosterone stimulation activated CD8+ T cells via both MR and GPER.
Rapid (non-genomic) aldosterone effects were distinguished from chronic (genomic) effects.
Both MR and GPER antagonists were used to demonstrate the dual receptor involvement in rapid aldosterone signaling in CD8+ cells.
This finding suggests aldosterone can activate T cells through both classical and non-classical steroid receptor pathways.
Results
Cortisol increased IFN-γ production in CD8+ T cells through MR.
The lack of 11βHSD2 expression in T cells means cortisol is not locally inactivated, allowing it to bind and activate MR.
IFN-γ production was enhanced by cortisol exposure in CD8+ cells.
This finding has implications for hypercortisolism (e.g., Cushing's syndrome) as a potential driver of similar T-cell-mediated organ damage.
Results
AT1R-specific CD8+ T-cell clones induced apoptosis of human endothelial cells expressing AT1R.
Functional cytotoxicity of AT1R-specific CD8+ clones toward human endothelial cells was directly assessed.
Endothelial cells expressing AT1R were used as targets in the cytotoxicity assay.
Apoptosis of endothelial cells was the demonstrated outcome, suggesting a mechanism for hypertension-mediated organ damage.
Discussion
The study identifies an adaptive autoimmune mechanism in primary aldosteronism involving autoreactive AT1R-specific CD8+ T cells.
Prior work had identified autoantibodies against AT1R in PA, suggesting a loss of immunological tolerance; this study extends that finding to the T-cell compartment.
The findings provide mechanistic insight into how steroid-driven T-cell activation may contribute to hypertension-mediated organ damage.
The authors propose relevance to both aldosteronism and hypercortisolism based on the shared MR-mediated cortisol effect.
What This Means
This research suggests that patients with primary aldosteronism (PA) — a condition where the adrenal glands overproduce the hormone aldosterone, causing high blood pressure — have an abnormal immune response targeting their own blood vessel cells. Specifically, the study found that PA patients have an expanded population of immune cells called CD8+ T cells that recognize a specific piece of the angiotensin II type-1 receptor (AT1R), a protein found on blood vessel walls. These 'autoreactive' T cells were shown in laboratory experiments to kill human endothelial (blood vessel lining) cells, providing a potential explanation for how PA causes organ damage beyond simply raising blood pressure.
The study also found that aldosterone itself — the very hormone that is overproduced in PA — can make these harmful T cells more active and more numerous. This happens through two different receptors on the T cells (MR and GPER), meaning aldosterone amplifies the immune attack on blood vessels through multiple pathways. Importantly, the stress hormone cortisol was found to have a similar activating effect on these T cells via MR, because the T cells lack an enzyme (11βHSD2) that would normally protect them from cortisol's effects. This suggests that conditions of excess cortisol, such as Cushing's syndrome, may trigger a similar autoimmune mechanism.
These findings matter because they reveal a previously unrecognized immune component to PA-related organ damage. This research suggests that in PA, high aldosterone levels not only raise blood pressure directly but also fuel an autoimmune attack on blood vessels, which could help explain why PA patients often suffer disproportionately severe cardiovascular complications compared to patients with equally elevated blood pressure from other causes. Understanding this mechanism could eventually open new avenues for treatment targeting this immune pathway.
Scarpa R, Piazza M, Caroccia B, Carraro S, Iacobone M, Torresan F, et al.. (2026). Immune signatures associated with human adrenocortical hypertension.. European journal of endocrinology. https://doi.org/10.1093/ejendo/lvag126