γδ T Cells Mediate Angiotensin II-Induced Hypertension and Vascular Injury

BACKGROUND: Innate antigen-presenting cells and adaptive immune T cells have been implicated in the development of hypertension. However, the T-lymphocyte subsets involved in the pathophysiology of hypertension remain unclear. A small subset of innate-like T cells expressing the gamma delta T cell receptor (TCR) rather than the alpha beta TCR could play a role in the initiation of the immune response in hypertension. We aimed to determine whether angiotensin (Ang) II caused kinetic changes in gamma delta T cells; deficiency in gamma delta T cells blunted Ang II-induced hypertension, vascular injury, and T-cell activation; and gamma delta T cells are associated with human hypertension. METHODS: Male C57BL/6 wild-type and Tcr delta(-/-) mice, which are devoid of gamma delta T cells, or wild-type mice injected IP with control isotype IgG or gamma delta T cell-depleting antibodies, were infused or not with Ang II for 3, 7, or 14 days. T-cell profiling was determined by flow cytometry, systolic blood pressure (SBP) by telemetry, and mesentery artery endothelial function by pressurized myography. TCR delta constant region gene expression levels and clinical data of a whole blood gene expression microarray study, including normotensive and hypertensive subjects, were used to demonstrate an association between gamma delta T cells and SBP. RESULTS: Seven-and 14-day Ang II infusion increased gamma delta T-cell numbers and activation in the spleen of wild-type mice (P< 0.05). Fourteen days of Ang II infusion increased SBP (P< 0.01) and decreased mesenteric artery endothelial function (P< 0.01) in wild-type mice, both of which were abrogated in Tcr delta(-/-) mice (P< 0.01). Anti-TCR gamma delta antibody-induced gamma delta T-cell depletion blunted Ang II-induced SBP rise and endothelial dysfunction (P< 0.05), compared with isotype antibody-treated Ang II-infused mice. Ang II-induced T-cell activation in the spleen and perivascular adipose tissue was blunted in Tcr delta(-/-) mice (P< 0.01). In humans, the association between SBP and gamma delta T cells was demonstrated by a multiple linear regression model integrating whole blood TCR delta constant region gene expression levels and age and sex (R-2= 0.12, P< 1x10(-6)). CONCLUSIONS: gamma delta T cells mediate Ang II-induced SBP elevation, vascular injury, and T-cell activation in mice. gamma delta T cells might contribute to the development of hypertension in humans.