The role of T cells in vascular aging, hypertension, and atherosclerosis

Abstract

Vascular dysfunction has emerged as a significant risk factor for the development of cardio- and cerebrovascular diseases (CVDs), which are currently the leading cause of morbidity and mortality worldwide. T lymphocytes (T cells) have been shown to be important modulators of vascular function in primary aging and CVDs, likely by producing inflammatory cytokines and reactive oxygen species that influence vasoprotective molecules. This review summarizes the role of T cells on vascular function in aging, hypertension, and atherosclerosis in animals and humans, and discusses potential T-cell targeted therapeutics to prevent, delay, or reverse vascular dysfunction.

Keywords: T cells; inflammation; oxidative stress; vascular dysfunction.

Figure 1.

T-cell subpopulations and differentiation. T-cell progenitors from hematopoietic stem cells (HSCs) in the bone marrow migrate to the thymus, committing to the T-cell lineage as CD3⁺ αβ or γδ T cells. Subpopulations of αβ T cells include CD4⁺ T-helper cells (T_H) or CD8⁺ cytotoxic cells (T_C), which upon antigen exposure differentiate into effector (T_EFF) (e.g., Th1, Th2, and Th17), regulatory (T_REG), angiogenic (T_ANG), and choline acetyltransferase (ChAT) producing T cells. Following resolution of an infection, some activated cells become quiescent memory T cells, categorized as central memory (T_CM) and effector memory (T_EM) T cells. T_CM can be reactivated in response to secondary infection to T_EM. Over time, T cells may become dysfunctional through T-cell exhaustion, immunosenescence, or cellular (replicative) senescence. Figure images were created with a licensed version of BioRender.com.

Figure 2.

Mechanisms of T-cell activation in aging and cardio- and cerebrovascular diseases (CVDs). T-cell activation is induced by the following mechanisms: 1a) The T-cell receptor (TCR) is presented with classical or neo-antigens via the major histocompatibility complex (MHC) on antigen presenting cells (APCs), such as dendritic cells or 1b) endogenous hormones or lipids bind to T-cell surface receptors, such as angiotensin-I (AT1R), β2-adrenergic, or low-density lipoprotein receptor (LDLR). 2) T-cell costimulation is needed to induce activation. For example, the B7 protein on APCs binds to the CD28 surface protein on T cells. 3) Following activation, T cells produce proinflammatory cytokines, cytotoxic molecules, and reactive oxygen species (ROS) that may contribute to cardiovascular and cerebrovascular disease (CVD) vascular risk factors. Over time, repetitive activation will result in a dysfunctional T-cell phenotype (e.g., immunosenescence, exhaustion, or cellular senescence). Inflammation and ROS may also promote a dysfunctional T-cell phenotype resulting in a feed-forward cycle. Other factors that may influence T-cell activation, and the inflammatory or oxidative T-cell phenotype include the endogenous T-cell renin-angiotensin-aldosterone system (RAAS), mitochondrial dysfunction, and the mechanical stress caused by elevated blood pressure. Figure images were created with a licensed version of BioRender.com.

Figure 3.

Proposed mechanisms of T-cell mediated vascular dysfunction or protection. Activated effector or memory T cells and dysfunctional T cells release inflammatory cytokines, cytotoxic molecules (e.g., granzyme k), and reactive oxygen species (e.g., superoxide, O₂⁻) that reduce endothelial nitric oxide (NO) bioavailability by inhibiting or uncoupling endothelial NO synthase (eNOS) or by producing peroxynitrite (ONOO⁻). NO produced in the endothelium diffuses into the smooth muscle where it induces vasodilation by binding to guanylyl cyclase (GC) resulting in increased cyclic guanosine monophosphate (cGMP) and cGMP-dependent protein kinase type I (cGKI) activity. Regulatory, angiogenic, and choline acetyltransferase (ChAT) T cells may protect the vasculature by inhibiting proinflammatory T cells or producing anti-inflammatory cytokines (IL-10), nitric oxide (NO), or vascular growth factors that increase angiogenesis. Figure images were created with a licensed version of BioRender.com.

Figure 4.

Causes of and therapeutics for inflammatory and dysfunctional T-cell subpopulations. Factors such as advancing age, classical and neo-antigens, oxidative stress from reactive oxygen species (ROS) or other oxidized molecules (superoxide, O₂⁻; NADPH oxidase; or isolevuglandins, isoLGs), and metabolic dysfunction (e.g., impaired mitochondrial respiration) drive T cells toward inflammatory effector (e.g., T_H1 and T_H17) or memory T cells or dysfunctional (e.g., immunosenescent, exhausted, or cellular senescent) subpopulations. Therapeutics such as exercise, supplements, and pharmaceuticals may clear these T-cell subpopulations to prevent or treat cardiovascular diseases. Figure images were created with a licensed version of BioRender.com.