Human T Cells From Resistant Hypertension Patients Promote Hypertension via TNF in humanized mice

Abstract

ObjectivePreclinical studies suggest a pivotal role of adaptive immunity, particularly T cells, in hypertension. However, due to the multifactorial pathogenesis, there is still no definitive evidence for a causal role of T cells in the development of hypertension in humans. We sought to determine whether T cells from patients with treatment-resistant hypertension (TRH) directly modulate blood pressure and vascular function in vivo. MethodsPeripheral blood mononuclear cells (PBMCs) from TRH patients and healthy controls (HC) were adoptively transferred into immunodeficient NSG-(KbDb)^null mice. Hypertension was induced by angiotensin II infusion for 14 days and monitored continuously by radiotelemetry. ResultFollowing T cell engraftment, blood pressure was assessed at baseline and during AngII infusion in both groups of recipient mice. At baseline, systolic blood pressure did not differ between both groups. However, mice receiving TRH-PBMCs developed a significantly higher systolic blood pressure following AngII compared with HC-PBMC recipients. Endothelial dysfunction in isolated perfused kidneys was more pronounced in AngII-challenged TRH-PBMC recipients compared to HC-PBMC recipients. TRH-PBMC recipients displayed elevated effector memory CD4 T cells and Th17 frequencies in spleen and kidney, along with markedly increased renal expression of human T cell-derived TNF. Overnight incubation of mouse aortic rings with human TNF induced endothelial dysfunction, indicating a causal role of T cell-derived TNF. As a proof of concept, TNF inhibition attenuated AngII-induced hypertension in TRH-PBMC-engrafted mice. ConclusionT cells from patients with treatment-resistant hypertension promote an exaggerated hypertensive response and endothelial dysfunction in PBMC-engrafted humanized mice, promoted by TNF-mediated mechanisms. These findings provide evidence that T cell-derived TNF may contribute to the pathogenesis of human hypertension.