Salik Naqvi

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 determinants^1,2. 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 secukinumab^5,6. 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.

1. Caillon A, Mian MOR, Fraulob-Aquino JC, Huo K-G, Ouerd S. γδ T Cells Mediate Angiotensin II-Induced Hypertension and Vascular Injury. Circulation. 2017;135(22):2155-2162. doi:https://doi-org.srv-proxy1.library.tamu.edu/10.1161/CIRCULATIONAHA.116.027058.
2. Carey RM, Bosworth HB, Whelton PK. Prevention and Control of Hypertension:: JACC Health Promotion Series. Journal of the American College of Cardiology. 2018;72(11):1278-1293. doi:https://doi.org/10.1016/j.jacc.2018.07.008.
3. Godfrey DI, Uldrich AP, Mccluskey J, Rossjohn J, Moody DB. The Burgeoning Family of Unconventional T Cells. Nature Immunology. 2016;17(2):214-214. doi:https://doi-org.srv-proxy1.library.tamu.edu/10.1038/ni.3298.
4. Chatterjee PD, Chiasson VLD, Seerangan GD, et al. Depletion of MHC Class II Invariant Chain Peptide or γ–δ T-cells Ameliorates Experimental Preeclampsia. Clinical Science. 2017;131(15):2047-2058. doi:10.1042/cs20171008.
5. Chiasson VL, Pakanati AR, Hernandez MJ, Young KR, Bounds KM, Mitchell. Regulatory T-Cell Augmentation or Interleukin-17 Inhibition Prevents Calcineurin Inhibitor–Induced Hypertension in Mice. Hypertension. 2017;70(1):183-191. doi:10.1161/hypertensionaha.117.09374.
6. Liu YM, Rafferty TW, Rhee SS, et al. CD8⁺ T cells Stimulate Na-Cl Co-transporter NCC in Distal Convoluted Tubules Leading to Salt-sensitive Hypertension. Nature Communications. 2017;8(1):1-14. doi:10.1038/ncomms14037.
7. Saleh MA, Norlander AE, Madhur MS. Inhibition of Interleukin-17A, But Not Interleukin-17F, Signaling Lowers Blood Pressure, and Reduces End-Organ Inflammation in Angiotensin II–Induced Hypertension. JACC: Basic to Translational Science. 2017;1(7):606-616. doi:10.1016/j.jacbts.2016.07.009.
8. Wang Z, Shi W, Liang X, Wang W, Liang J. Association of Interleukin 17 / Angiotensin II with Refractory Hypertension Risk in Hemodialysis Patients. African Health Sciences. 2016;16(3):766. doi:10.4314/ahs.v16i3.17.