Activation of Human T Cells in Hypertension

Abstract

Emerging evidence supports an important role for T cells in the genesis of hypertension. Because this work has predominantly been performed in experimental animals, we sought to determine whether human T cells are activated in hypertension. We employed a humanized mouse model in which the murine immune system is replaced by the human immune system. Angiotensin II increased systolic pressure to 162 mm Hg vs. 116 mm Hg for sham treated animals. Flow cytometry of thoracic lymph nodes, thoracic aorta and kidney revealed increased infiltration of human leukocytes (CD45+) and T lymphocytes (CD3+ and CD4+) in response to angiotensin II infusion. Interestingly, there was also an increase in the memory T cells (CD3+/CD45RO+) in the aortas and lymph nodes. Prevention of hypertension using hydralazine and hydrochlorothiazide prevented the accumulation of T cells in these tissues. Studies of isolated human T cells and monocytes indicated that angiotensin II had no direct effect on cytokine production by T cells or the ability of dendritic cells to drive T cell proliferation. We also observed an increase in circulating IL-17A producing CD4+ T cells and both CD4+ and CD8+ T cells that produce IFN-γ in hypertensive compared to normotensive humans. Thus, human T cells become activated and invade critical end-organ tissues in response to hypertension in a humanized mouse model. This response likely reflects the hypertensive milieu encountered in vivo and is not a direct effect of the hormone angiotensin II.

Transcriptome-Wide Analysis Identifies Novel Associations With Blood Pressure

“…3,37 For instance, selective ablation of lysozyme M-positive myelomonocytic cells attenuated angiotensin II–induced hypertension. 5 Likewise, Itani et al 4 showed that human T cells become activated by hypertensive stimuli, such as angiotensin II.…”

“…2,3 Hypertension is determined by multiple factors, and during the past years, the immune system (mainly T cells) and inflammatory processes have emerged as key contributors to elevated blood pressure (BP) in several experimental animal and human models. 4,5 A shared pathophysiology with manifest cardiac disease is suggested. 3,6 Nevertheless, there is also a substantial genetic heritability of 30% to 60% for hypertension.…”

Oxidative Stress, Inflammation, and Vascular Aging in Hypertension

“…74 They are characterized by loss of CD28 marker and appearance of CD57 and functionally produce tumor necrosis factor-α and interferon-γ, which affect vascular changes. 75 While early studies have shown that T cells are key in hypertension, 76,77 recent clinical studies indicate that their role is related to a close interaction with other elements of innate, cellular, and humoral immunity. 76 In particular, B cells seem to be essential in hypertension, and their lack is associated with diminished vascular oxidative stress.…”

“…75 While early studies have shown that T cells are key in hypertension, 76,77 recent clinical studies indicate that their role is related to a close interaction with other elements of innate, cellular, and humoral immunity. 76 In particular, B cells seem to be essential in hypertension, and their lack is associated with diminished vascular oxidative stress. 78 Obesity is related to particularly high immune activation that may contribute to hypertension both nonspecifically through cytokines and adipocytokines, as well as through more specific mechanisms.…”

“…Increased oxidative stress in dendritic cells leads to increased capacity for antigen presentation, which involved Nox2 and isolevuglandins, which increase the ability of dendritic cells to drive T-cell proliferation. 76,87 Pattern recognition receptors, such as TLR4, have recently been implicated in the regulation of antigen presenting cell function in hypertension. This activates inflammatory signaling through My88D and activation of nuclear factor-κB, important in cardiac and renal damage and potentially in the development of high BP.…”