Inhibition of T cell Costimulation Prevents the Development of Hypertension

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Classically, T cell activation requires antigen recognition by the T cell receptor and costimulation. The latter often involves interaction between B7 ligands (CD80 and CD86) on antigen presenting cells (APCs) with the T cell co receptor CD28. We hypothesized that inhibition of costimulation would reduce hypertension and its associated vascular inflammation. Blockade of B7 dependent costimulation with the human recombinant fusion protein, CTLA4Ig, prevented both Ang II (490 ng/kg/min) and DOCA salt induced hypertension in mice (Ang II: 168 ± 1.5 Vs 139 ± 2.8 mmHg, P<0.001; DOCA: 153 ± 3.2 Vs 135 ± 2.7 mmHg, P<0.001). FACS revealed that circulating T cell activation and vascular T cell infiltration caused by these hypertensive stimuli was completely abrogated by CTLA4Ig. Additionally, B7KO mice were protected from Ang II induced hypertension (154 ± 2.5 Vs 124 ± 3.3 mmHg, P<0.001) and vascular T cell infiltration. Engrafting B7 mice with WT bone marrow restored Ang II induced hypertension. Finally, we found that angiotensin II infusion increased the percent of CD11c+CD86+ cells in lymph nodes, suggesting APC activation in hypertension. These findings indicate that T cells are activated classically in hypertension, suggestive of a possible neoantigen produced by or in response to hypertensive stimuli. This study suggests a novel approach to hypertension treatment. Funded by NIH R01 HL39006 and PPG HL58000.