Adv Physiol Educ 38: 20–24, 2014;
Refresher Course
The immune system in hypertension
Daniel W. Trott and David G. Harrison
Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
Submitted 13 June 2013; accepted in final form 20 December 2013
Trott DW, Harrison DG. The immune system in hypertension. Adv
Physiol Educ 38: 20–24, 2014; doi:10.1152/advan.00063.2013.—While
hypertension has predominantly been attributed to perturbations of the
vasculature, kidney, and central nervous system, research for almost
50 yr has shown that the immune system also contributes to this
disease. Inflammatory cells accumulate in the kidneys and vasculature
of humans and experimental animals with hypertension and likely
contribute to end-organ damage. We and others have shown that mice
lacking adaptive immune cells, including recombinase-activating
gene-deficient mice and rats and mice with severe combined immu-
nodeficiency have blunted hypertension to stimuli such as ANG II,
high salt, and norepinephrine. Adoptive transfer of T cells restores the
blood pressure response to these stimuli. Agonistic antibodies to the
ANG II receptor, produced by B cells, contribute to hypertension in
experimental models of preeclampsia. The central nervous system
seems important in immune cell activation, because lesions in the
anteroventral third ventricle block hypertension and T cell activation
in response to ANG II. Likewise, genetic manipulation of reactive
oxygen species in the subfornical organ modulates both hypertension
and immune cell activation. Current evidence indicates that the
production of cytokines, including tumor necrosis factor-␣, interleu-
kin-17, and interleukin-6, contribute to hypertension, likely via effects
on both the kidney and vasculature. In addition, the innate immune
system also appears to contribute to hypertension. We propose a
working hypothesis linking the sympathetic nervous system, immune
cells, production of cytokines, and, ultimately, vascular and renal
dysfunction, leading to the augmentation of hypertension. Studies of
immune cell activation will clearly be useful in understanding this
common yet complex disease.
T cell; cytokines; angiotensin; subfornical organ; costimulation
IN THE 1960S, a role for the immune system in the development
of hypertension was first discovered. Several recent investiga-
tions have further defined the role of immune system, partic-
ularly the adaptive immune system, in hypertension, provided
novel insights into the genesis of hypertension, and identified
novel targets for the treatment of hypertension. The purpose of
this review was to summarize recent discoveries by our labo-
ratory and others on the role of the immune system in hyper-
tension.
Early Studies in Immunity and Hypertension
The concept that the immune system contributes to hyper-
tension had its genesis in the 1960s, when Grollman et al. (40,
56) demonstrated that immunosuppression blunted hyperten-
sion in a model of renal infarction and that transfer of lym-
phocytes from rats with renal infarction induced hypertension
in previously nonhypertensive animals. Later, Svenson found
that hypertension was not maintained in thymectiomized or
Address for reprint requests and other correspondence: D. G. Harrison,
Division of Clinical Pharmacology, Dept. of Medicine, Robinson Research
Bldg., Rm. 536, Vanderbilt Univ., Nashville, TN 37232-6602 (e-mail: david.
g.harrison@vanderbilt.edu).
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doi:10.1152/advan.00063.2013.
athymic nude mice with renal infarction (46). In the 1980s, Ba
et al. (2) found that transplanting the thymus from a Wistar-
Kyoto (WKY) rat to a spontaneously hypertensive rat (SHR)
resulted in a decrease in blood pressure in the SHR (2). Blood
pressure was also lowered in SHRs with treatment by either
anti-thymocyte serum or the immunosuppressive drug cyclo-
phosphamide (5, 12). Nerve growth in the thymus of SHR was
found to be greater than that of WKY rats, suggesting a neural
component of immune cell activation in hypertension (42).
Rodruiguez-Iturbe et al. (43) found that immunsupression with
mycophenlate mofetil blunted salt-induced hypertension after
ANG II infusion. In the early 2000s, Muller and Luft (35, 36,
49) conducted a series of investigations showing that NF-␬B
and ROS play roles in ANG II-induced end-organ damage.
More recently, advances in genetic mouse models and knowl-
edge of immunology prepared the way for discoveries that
would lead to further understanding of the importance of the
immune system in hypertension.
T Cells and Hypertension
In 2007, our laboratory (18) published a study demonstrating
that T cells contribute to the development of hypertension. In
this study, mice lacking recombinase-activating gene 1 (Rag-
1⫺/⫺ mice) were used as these mice cannot generate functional
T cell receptors or B cell antibodies and thus lack both T and
B lymphocytes. The increase in blood pressure caused by
either ANG II or DOCA salt was significantly blunted in
Rag-1⫺/⫺ mice, suggesting that either T or B cells mediate
overt hypertension. Rag-1⫺/⫺ mice did not exhibit increased
vascular superoxide production and endothelial dysfunction.
The hypertensive response to ANG II was restored when
Rag-1⫺/⫺ mice received adoptive transfer of T cells but not B
cells. In wild-type mice, ANG II increased circulating CD69⫹,
CCR5⫹, and CD44high T cells, markers of effector memory T
cells. In addition, T cells accumulated in the perivascular
adipose tissue of the aorta. The results of this study indicate
that T cells play a major role in hypertension. Supporting the
role of T cells in hypertension, severe combined immunodefi-
cieny mice have also been shown to be protected against
hypertension and exhibit reduced albuminuria and renal dam-
age (10). Recently, Mattson et al. (32) deleted the Rag1 gene in
Dahl salt-sensitive rat using zinc finger nuclease technology
and have shown that this attenuates blood pressure, albumin-
uria, and kidney damage. Thus, T cells seem to contribute to
the development of various forms of hypertension in different
strains of mice and in rats.
Role of the Central Nervous System in Immune-Mediated
Hypertension
The blood vessels, kidney, and central nervous system
(CNS) have all been shown to contribute to the development of
hypertension. Interestingly, T cells may represent a link be-

IMMUNE CELLS AND HYPERTENSION
tween these tissues. Lymphoid tissues are rich in sympathetic
nerves (14). Ganta et al. (17) have shown that intracerebroven-
tricular infusion of ANG II increased sympathetic nerve activ-
ity to the spleen and increased expression of multiple cytokines
in the spleen. Our laboratory has preformed a series of inves-
tigations on the role of the CNS in mediating T cell activation.
The circumventricular organs (CVO) are highly vascularized
and have an incomplete blood-brain barrier and can therefore
be influenced by circulating hormones like ANG II. In addi-
tion, the CVO, and in particular, the subfornical organ (SFO),
are important in both sending and receiving central signals that
regulate cardiovascular function and electrolyte balance. De-
letion of CVO extracellular (ec)SOD, using Cre-lox technol-
ogy, provides a model to determine the role of central oxidative
stress in hypertension. ecSOD deletion increased ROS levels in
the CVO, increased heart low-frequency to high-frequency
heart rate variability (indicative of increased sympathetic ner-
vous activity), and elevated blood pressure (25). In addition,
when mice with ecSOD deleted in the CVO were infused with
ANG II at a dose that does not cause hypertension in normal
mice (140 ng·kg⫺1·min⫺1), blood pressure was significantly
elevated and was accompanied by aortic T cell infiltration.
Interestingly, in a separate investigation, when ecSOD was
specifically deleted in vascular smooth muscle, despite in-
creases in vascular ROS, blood pressure and T cell responses
were not altered compared with controls (27).
NADPH oxidases are major sources of superoxide anion
production in mammalian cells. The subunit p22phox mediates
trafficking of NADPH oxidase catalytic subunits to the cell
membrane and is required for enzyme complex assembly and,
ultimately, superoxide production. Complementing the studies
that used deletion of ecSOD, our laboratory (26) also deleted
p22phox in the SFO in a similar manner. Deletion of p22phox in
the SFO blunted the pressor response to ANG II and decreased
sympathetic outflow as assessed by heart rate variability. In
addition, p22phox deletion abolished ANG II-induced aortic T
cell infiltration. This study is in keeping with findings that
intracerebroventricular injections of a superoxide scavenger
reduces sympathetic drive, blood pressure, and renal damage in
salt-induced hypertension in rats (16).
Supporting the role of the central nervous system, lesions in
the anteroventral third cerebral ventricle (AV3V), a region
which includes the SFO, can prevent ANG II-induced hyper-
tension (7, 30). In addition, AV3V lesions protect against T
cell activation and aortic infiltration in response to ANG II
(30). This is of particular importance as it demonstrates that
ANG II-induced T cell activation is not due to direct actions of
ANG II on T cells but rather that central signals are required
for T cell activation. Interestingly, mice infused with norepi-
nephrine become hypertensive and exhibit T cell activation and
aortic infiltration even after AV3V lesions. This supports the
concept that sympathetic drive, and its attendant release of
norepinephrine, likely mediates T cell activation and hyperten-
sion. In addition to the important role of the CNS, peripheral
mechanisms appear to also contribute to T cell activation and
vascular inflammation. Treatment with the vasodilator hydral-
zine to normalize blood pressure prevents T cell activation and
vascular inflammation induced by ANG II infusion (30). This
suggests that T cells may respond to elevations in pressure and
that afferent nerves may activate central mechanisms in a
feedforward manner to induce CVO oxidative stress, sympa-
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21
thetic outflow, further T cell activation, and overt hypertension.
More recently, T cells have been shown to contribute to
stress-induced hypertension (31). We exposed mice to 7 days
of stress using a combination of restraint and cage switching.
This stress paradigm resulted in increased blood pressure,
activation of circulating T cells, and aortic T cell infiltration.
Rag-1⫺/⫺ mice were protected from stress-induced hyperten-
sion, and adoptive transfer of T cells restored the hypertensive
response. These findings underscore the crucial role of the
CNS in orchestrating the T cell response leading to hyperten-
sion.
T Cell Subtypes, Cytokines, and Mechanisms of Activation
The above studies demonstrated that T cells contribute to the
development of hypertension; however, they do not provide
extensive insights into the subsets of T cells involved. CD4⫹ T
cells have been generally classified as either T helper (Th)1 or
Th2, depending on their activation markers and cytokine pro-
duction (34). Th17 cells are a newly characterized subset of T
cells; these cells produce the cytokine IL-17 and contribute to
numerous autoimmune diseases, obesity, and cardiovascular
disease (13, 48, 57). To investigate the role of IL-17 in
hypertension, our group studied IL-17a⫺/⫺ mice. These mice
exhibited a similar initial increase in blood pressure as wild-
type mice in response to ANG II; however, after 7 days, blood
pressure dropped in IL-17a⫺/⫺ mice (28). The ANG II-induced
aortic T cell infiltration observed in wild-type mice was abol-
ished in IL-17a⫺/⫺ mice, as were increases in vascular oxida-
tive stress and endothelial dysfunction. Recent reports have
shown that direct infusion of IL-17a mediated hypertension
and endothelial dysfunction in mice (37) and that IL-17 medi-
ated placental oxidative stress, resulting in hypertension during
pregnancy in rats (11).
In addition to IL-17, other cytokines have been implicated in
the pathogenesis of hypertension. Etanrecept, a TNF-␣ antag-
onist, is effective in preventing hypertension (18, 50, 52). IL-6
knockout mice are also protected from ANG II-induced hyper-
tension (6, 24, 45). Interferon (IFN)-␥ is upregulated in the
kidneys of hypertensive mice (10), and inhibition of IFN-␥
prevents ANG II-induced end-organ damage (29). Taken to-
gether, these observations suggest that hypertension is medi-
ated by multiple proinflammatory T cell subsets. In accordance
with this concept, T regulatory (Tregs) cells, which act to
restrain proinflammatory T cells, attenuate hypertension-in-
duced end-organ damage in mice (22) and blunt hypertension
in rats (53).
Classically, T cells require two signals for activation: 1) interaction
of the T cell receptor with an antigen presented in the context
of a major histocompatibilty complex and 2) stimulation of
costimulatory molecules on the T cell by ligands on the
antigen-presenting cell (1). A major costimulatory molecule on
T cells is CD28, which is bound by the B7 ligands CD80 and
CD86 of the antigen-presenting cell. Ligation of the T cell
receptor in the absence of costimulation leads to T cell apo-
ptosis (15). The pharmacological agent CTLA4-Ig inhibits
costimulation by binding to B7 ligands on antigen-presenting
cells. To determine whether costimulation plays a role in
hypertension, our laboratory used both pharmacological inhi-
bition of costimulation with CTLA4-Ig and a genetic approach
with B7-deficient (B7⫺/⫺) mice. CTLA4-Ig treatment blunted
Refresher Course
22 IMMUNE CELLS AND HYPERTENSION
blood pressure, T cell activation, and vascular infiltration in
both ANG II- and DOCA salt-induced hypertension (54).
CTLA4-Ig treatment also abolished T cell production of
TNF-␣ and IFN-␥ induced by ANG II. Similar results were
observed in B7⫺/⫺ mice, which lack B7 ligands. These obser-
vations suggest that T cell receptor ligation and costimulation
are necessary for T cell activation in hypertension.
The Innate Immune System and Hypertension
The role of the adaptive immune system in experimental
hypertension has been well characterized; however, less is
known about the role of the innate immune system. Recently,
Abboud et al. (19) demonstrated that, in WKY rats, the chole-
neric agonist nicotine results in an anti-inflammatory response
in splenic macrophages; in contrast, nicotine induced a proin-
flammatory response in macrophages from SHRs and enhanced
Toll-like receptor-mediated cytokine release. In addition,
perivascular macrophage infiltration has been observed in ex-
perimental hypertension in mice (3). Inflammatory cytokines,
IL-1␤, and IL-6 are elevated in SHRs compared with WKY
rats; this can be reversed by treatment with an angiotensin-
converting enzyme inhibitor (33). Similarly, ANG II receptor
blockade prevented lipopolysaccharide-induced inflammatory
responses of innate immune cells in the rat spleen (44). In
humans, white blood cells from essential hypertensive patients
produced more IL-1␤ and IL-6 when stimulated with lipopoly-
saccharide compared with controls (41). These observations
are consistent with monocyte activation in hypertension. How
the innate and adaptive immune systems interact in the devel-
opment of hypertension is not well understood and is an
important topic for future study.
The Immune System and Preeclampsia
Preeclampsia is characterized by the onset of hypertension
during pregnancy accompanied by proteinuriea. Preeclampsia
is associated with the production of autoantibodies that stim-
ulate the ANG II type 1 (AT1) receptor (55), and infusion of
these antibodies can induce preeclampsia-like symptomps in
pregnant mice (60). More recently, it has been shown that a
specific subset of B cells produces these antibodies (21).
Depletion of B cells using the anti-CD20 antibody rituximab
blunts the blood pressure response in the reduced uterine
perfusion pressure rat model of preeclampsia (23). Adoptive
transfer of CD4⫹ T cells from reduced uterine perfusion
pressure rats to normal pregnant rats results in increased blood
pressure (39). This response is blunted by either rituximab or
AT1 antagonism, suggesting an important role of cross-talk
between T and B cells in preeclampsia. Supporting the role of
T cells in preeclampsia, mice deficient in the cytokines IL-4 or
IL-10, which skew T cells to an anti-inflammatory phenotype,
develop preeclampsia-like symptoms when pregnant (8, 9).
The proinflammatory cytokine IL-17 mediates placental oxi-
dative stress and increases in blood pressure in pregnant rats
(11). Together, these observations support a role for the adap-
tive immune system in preeclampsia where T and B cells act in
a synergistic manner.
Pulmonary Hypertension and the Immune System
It has long been postulated that autoimmunity and inflam-
mation is involved in pulmonary hypertension (38). In addi-
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tion, T cells, B cells, and macrophages are present in the lungs
of patients with pulmonary hypertension (51). Recently, a role
of anti-inflammatory Tregs cells has been indentified in exper-
imental pulmonary hypertension (47). In this study, in response
to VEGF receptor 2 antagonism, athymic rats, which lack T
cells, developed perivascular inflammation, including infiltra-
tion of B cells and macrophages in the lung and pulmonary
hypertension. The authors then reconstituted different T cell
subsets in these animals and found that CD4⫹ Tregs cells acted
to blunt pulmonary vascular inflammation and the development
of pulmonary hypertension. In a similar manner, Tregs cells
appear to act to restrain experimental systemic hypertension in
both mice and rats (3, 22, 53).
The Immune System in Human Hypertension
Although the majority of studies implicating the immune
system in hypertension have been performed in experimental
animals, a limited number of investigations have examined the
role of the immune system in human hypertension. IL-6 and
TNF-␣ are positively correlated with blood pressure in humans
(4). In a small study, patients with either rheumatoid arthritis or
psoriasis who also had essential hypertension were treated with
mycophenlate mofetil, resulting in significantly lowered sys-
tolic and diastolic blood pressure (20). Recently, circulating
proinflammatory CD8⫹ T cells have been indentified in hyper-
tensive patients (58). These cells generate IFN-␥ and TNF-␣
and exhibit loss of CD28 and gain of CD57, which is consistent
with a proinflammatory, senescent T cell phenotype. These
patients also exhibited increased circulating chemokines,
which serve as T cell attractants.
Conclusions and Future Directions
In summary, it has been known for almost 50 yr that immune
cells contribute to hypertension; in the last several years,
investigations from our group and others have demonstrated
the importance of T cells in the development of hypertension.
In light of the data discussed here, we have formulated a
working hypothesis for the development of overt hypertension.
As shown in Fig. 1, hypertensive stimuli, such as ANG II or
salt, leads to an initial elevation in blood pressure, consistent
Hypertensive stimuli
ANG II, salt, stress, aldosterone
CNS inflammation and
oxidative stress
Vasoconstriction
Vascular hypertrophy
Sympathetic outflow
T cell Severe hypertension
Pre-hypertension - “Barotrauma”
Neoantigen formation and
presentation by dendritic cells Sodium
Volume Retention
Fig. 1. Working hypothesis describing the role of immune cells in hyperten-
sion. CNS, central nervous system.

IMMUNE CELLS AND HYPERTENSION
with clinical “prehypertension,” which results in protein mod-
ifications, possibly due to oxidative modifications. These al-
tered proteins serve as neoantigens that no longer recognized as
self, are processed and presented by dendritic cells, and pro-
mote T cell activation. In concert, afferent signals to the CNS
result in increased sympathetic outflow contributing to T cell
activation. Activated T cells infiltrate the kidney and vascula-
ture and produce cytokines that promote renal Na⫹ and water
retention and, in the vasculature, vasoconstriction and remod-
eling. Together, these alterations result in overt hypertension.
The observation that hydralizine treatment abolished the T cell
response suggests that signals from the periphery operate in a
feedforward manner to signal the CNS to increase central
sympathetic drive and mediate overt hypertension. An impor-
tant point is that the T cell response is independent of the
model of experimental hypertension, T cell responses have
been observed in mice in response to ANG II, DOCA salt, and
norepinephrine. In rats, this response has been observed in both
salt-sensitive and genetic models. Emphasizing this point is the
recent study of Zhang et al. (59), where ANG II receptors were
specifically deleted in mouse T cells using Cre-lox technology.
These mice were not protected against ANG II-induced hyper-
tension, and, surprisingly, kidney damage in response to ANG
II was exacerbated (59). These observations indicate that the T
cell response in hypertension is independent of direct actions of
ANG II on T cells. We believe, based on the studies of the
CNS, that central signals mediate T cell activation in a variety
of hypertension models. Recent observations by Abboud et al.
(19) have suggested that central signals regulate the innate
immune system in hypertension as well. It should be noted that
the model for the immue system in hypertension outlined here
is a working hypothesis; the precise mechanisms, particularly
the initiating factors in the development of hypertension, are as
yet unknown. Our hypothesis will almost certainly require
refinement as new information comes available.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: D.W.T. and D.G.H. conception and design of re-
search; D.W.T. and D.G.H. prepared figures; D.W.T. and D.G.H. drafted
manuscript; D.W.T. and D.G.H. approved final version of manuscript.
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