Abstract 001: Hypertension Induces Heightened Activity of the Adaptive Immune System

Abstract

Adaptive immunity plays a key role in the pathogenesis of hypertension, but how does hypertension affect immunity? To study this, splenic dendritic cells (DC) and peritoneal macrophages were isolated from normotensive and hypertensive angiotensin II (AngII)-infused C57BL6/J mice (490 ng/kg/min, 2 wk). These antigen presenting cells (APCs) were loaded with ovalbumin (OVA) or the OVA MHC class I epitope SIINFEKL (SKL) for 3h. Then, splenocytes from OT-I mice, containing OVA-specific, CD8 + T cells (OT-I cells), were added for 4h. Flow cytometry showed significantly more activated T cells expressing CD69 when stimulated with APCs from AngII-treated mice than equivalent cells from naïve mice (As example, DC+OVA: 2.9 ± 0.4% vs. 1.8 ± 0.3% ,P<0.05; DC+SKL: 13.9 ± 0.9 % vs. 7.4 ± 1.1%, P<0.01;). To study antigen presentation in vivo, we immunized AngII and sham treated mice with OVA and adjuvant. Consistently more OVA-specific CD8 + T cells were induced in the blood (2.7 ± 0.2% vs. 1.2 ± 0.4%, P<0.05) and the spleen (2.6 ± 0.3% vs. 1.5 ± 0.2%, P<0.05) of hypertensive mice vs. sham when measured by flow using a H-2k b -SKL tetramer. RIP-mOVA mice were also used to study if hypertension affects APC cross-presentation of self-antigens. This transgenic mouse line expresses membrane-bound OVA in pancreatic islet β cells and kidney proximal tubular cells. When OT-I cells (5x10 6 ) are injected into RIP-mOVA mice, they activate by cross-presentation of OVA and cause insulitis and diabetes. RIP-mOVA mice were made hypertensive with either AngII or L-NAME. When OT-I cells were infused into hypertensive RIP-mOVA mice, they rapidly developed much higher blood glucose levels as compared to equivalently treated normotensive RIP-mOVA mice. For example, comparing mice 3 weeks after AngII and 1 wk after OT-I cells to normotensive mice 1 wk after OT-I cells, blood glucose was 331 ± 47 mg/dl in the hypertensive mice vs. 168 ± 39 mg/dl in the normotensive controls. Also, far more pancreatic islets were infiltrated by T cells in the hypertensive mice (AngII 78%, 31 of 40; L-NAME 72%, 21 of 29; control 13%, 10 of 75). In conclusion, hypertension itself is associated with higher activity of APC presentation of foreign and self-antigens which may explain why hypertension induces inflammation.