Role of T-cell activation in salt-sensitive hypertension

Abstract

The contributions of T lymphocytes to the pathogenesis of salt-sensitive hypertension has been well established. Under hypertensive stimuli, naive T cells develop into different subsets, including Th1, Th2, Th17, Treg, and cytotoxic CD8⁺ T cells, depending on the surrounding microenviroment in organs. Distinct subsets of T cells may play totally different roles in tissue damage and hypertension. The underlying mechanisms by which hypertensive stimuli activate naive T cells involve many events and different organs, such as neoantigen presentation by dendritic cells, high salt concentration, and the milieu of oxidative stress in the kidney and vasculature. Infiltrating and activated T subsets in injured organs, in turn, exert considerable impacts on tissue dysfunction, including sodium retention in the kidney, vascular stiffness, and remodeling in the vasculature. Therefore, a thorough knowledge of T-cell actions in hypertension may provide novel insights into the development of new therapeutic strategies for patients with hypertension.

Keywords: T cell; end-organ damage; hypertension; salt.

Fig. 1.

Distinct T-lymphocyte subsets are crucial in hypertension. Th1, Th17, γδ T, and T regulatory (Treg) subpopulations promote or suppress the genesis of hypertension through proinflammatory cytokines, including TNF-α, IFN-γ, and IL-17, or anti-inflammatory cytokines such as IL-10, respectively. The relationships between Th2, Th9, or Tfh cells and hypertension are not clear and need to be further investigated. Some differentiated T-effector cells convert to memory T cells, and memory T cells will become T-effector cells again in antigen-specific recall responses.

Fig. 2.

Proposed mechanisms by which hypertensive stimuli activate T lymphocytes. Hypertensive stimuli, such as salt or ANG II, promote T-cell activation through various mechanisms. Oxidant stress induced by hypertensive stimuli causes the generation of neoantigens, such as isoketal adducts in dendritic cells. T cells recognize modified autoantigens presented by dendritic cells and then mature and differentiate into activated T cells, producing a variety of cytokines, including IL-17, TNF-α, and IFN-γ, eventually leading to the development of hypertension. Additionally, hypertensive stimuli cause vascular endothelial cell and kidney damage, and augmented sympathetic outflow, which can further activate T cells. ROS, reactive oxygen species; DAMPs, damage-associated molecular patterns; PIGF, placental growth factor.

Fig. 3.

High salt concentrations modulate T-cell differentiation. Increased sodium promotes the development of IL-17-producing CD4⁺ T cells in a DC-dependent or -independent manner. Moreover, high salt impairs immunosuppressive functions of Tregs. These events coordinately underpin hypertension.

Fig. 4.

Proposed roles of T cells in multiple organ dysfunction. Inflammatory-activated T cells infiltrate and accumulate in major target organs, including the kidney and vasculature, and then produce a variety of deleterious mediators to cause organ injury. The net effects of T-cell activation on sympathetic outflow in hypertension are complex and will require further study. Treg cells as anti-inflammatory cells normalize vascular and kidney function through anti-inflammatory cytokine IL-10. Another particular subset of CD4⁺ T cells, termed the CD4⁺ T_ChAT subset, plays a homeostatic role in vasorelaxation and regulation of blood pressure.