The Role of γδ T Cells in Mediating Angiotensin II-Induced Hypertension and Vascular Injury
Introduction. Hypertension (HTN) is classically defined as blood pressure of greater than 130/80 on multiple occasions2. It can occur at any age, is ranked first in cause of disability-adjusted life-years worldwide, and is prone to genetic, environmental, and social determinants1,2. Its prevalence continues to rise in the face of an incomplete heredity – HTN genes explain up to 30-50% heredity but cannot explain the phenotypical variation and disease risk of primary HTN, suggesting other mediators at play.1 The adaptive and innate immune system may play an extensive role in mediating HTN through the renin-angiotensin-aldosterone system (RAAS) –CD8+ T cells are abundant in mineralocorticoid (MR) and angiotensin receptors and produce IFN-γ, elevating BP downstream3. Narrower cell niches like γδ T cells seemingly demonstrate substantial roles in HTN via IL-17 release, causing endothelial damage, HTN, and end organ damage.7 These findings suggest promising novel routes for immunotherapy in HTN. Methods. Genetic mouse models were utilized. WT mice, “antibody-free” controls, and experimental mice were injected with γδ T cell-depleting antibodies1. Pregnant pre-eclamptic mice with HTN had their γδ T-cell load measured.4 Calcineurin inhibitor (CNI)-treated hypertensive mice were administered IL-17-neutralizing antibodies and secukinumab5,6. In salt-mediated mice HTN models, adoptive CD8+ T cell transfer was performed.6 In Ang II-infused mice, flow cytometry determination assessed the immune cells and cytokines involved.7 ESRD patients received serum ELISA to determine angiotensin II and IL-17 levels in well-controlled vs. resistant HTN phenotypes.8 All experiments utilized standard controls. Results. Mice injected with γδ T cell-depleting antibodies demonstrate 50% decreases in SBP compared with WT mice & “antibody-free” controls.1 Adoptive CD8+ T cell transfer in mice precipitates massive immune infiltration and salt-mediated HTN that is both interleukin-mediated and cell-mediated, leading to upregulation of NCC pumps in mice kidneys and spleen.6 Ang II infusion potentiates CD3+ IL-17A+ and CD3+ IL-17F+ cell proliferation in mice kidney and aortae, potentiates HTN, TGF-β and ROS production, and causes end organ damage. Integrated mean fluorescence evidences that γδ T cells and (to a lesser extent) CD4+ TH17 cells are primary producers of IL-17A and IL-17F in HTN.6,7 γ/δ T cell-depleted mice demonstrate resistance to HTN pre-eclamptic phenotypes.4 ESRD patients with resistant HTN demonstrate higher angiotensin II and IL-17 levels.8 IL-17A proves most amenable to inhibition and CNI-treated mice demonstrate attenuated HTN following secukinumab treatment.5,7 Conclusions. Studies suggest that γδ T cells mediate RAAS and HTN via IL-17 production. Inhibition of either can attenuate HTN in mice models.
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