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Journal of Hypertension:
doi: 10.1097/HJH.0b013e3283638b52
Editorial Commentaries

Immune mechanisms in hypertension: how do T-regulatory lymphocytes fit in?

Schiffrin, Ernesto L.a,b

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aLady Davis Institute for Medical Research

bDepartment of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, PQ, Canada

Correspondence to Ernesto L. Schiffrin, CM, MD, PhD, FRSC, FRCPC, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Côte-Ste-Catherine Rd., #B-127, Montreal, PQ, Canada H3T 1E2. Tel: +1 514 340 7538; fax: +1 514 340 7539; e-mail: ernesto.schiffrin@mcgill.ca/http://www.ladydavis.ca/en/ernestoschiffrin

Low-grade inflammation and immunity are increasingly recognized as mechanisms that play roles in the pathophysiology of different forms of cardiovascular disease including hypertension. Indeed, immune cells can be found in the adventitia of blood vessels and in the kidney and heart. What cells are mediating the role of immunity and inflammation in hypertension? In this issue, Kassan et al.[1] review the participation of T-regulatory lymphocytes in hypertension. It may be important to remember which are the different types of immune cells that are involved. First, we must note that the immune system comprises both innate and adaptive immunity. Innate immune mechanisms are those that are available for immediate defense of the organism and respond to stimulation of pattern recognition receptors (PRRs) such as Toll-like receptors, which are receptor proteins that recognize specific patterns shared either by groups of pathogens, the pathogen-associated molecular patterns, or PRRs that recognize damage-associated molecular patterns [2]. Cells involved include monocyte/macrophages (which come in flavours such as M1, proinflammatory, and M2, reparative and profibrotic), and natural killer cells (which express CD161 [NK1.1] but do not express the T-cell marker CD3, T-cell receptors, or immunoglobulin B cell receptors). Natural killer cells should not be confused with natural killer T cells, a subset of CD1d-restricted T lymphocytes expressing T-cell receptors and CD4 or CD8, as well as CD161, which is the natural killer cell-associated marker. Natural killer T lymphocytes are part of the adaptive immune system, and produce interferon (IFN)-γ and interleukin (IL)-2, IL-4, and TNF-α. Dendritic cells, which are antigen-presenting cells activated by monocyte/macrophages, together with natural killer cells accumulate in the perivascular fat and adventitia of blood vessels as well as the interstitium of the kidney and heart, and contribute to activate B and T lymphocytes that mediate adaptive immune responses [3,4]. Thus, innate immune activation will be followed by the adaptive immune response, and in tissues such as the vasculature, the heart and the kidney, all these cellular elements may be found.

When we have infused angiotensin (Ang) II into mice with a mutation in the Csf1 gene (the gene of macrophage colony-stimulating factor) [5], which as a consequence are deficient in vascular macrophages, or induced deoxycorticosterone (DOCA)-salt hypertension in these [6], blood pressure (BP) did not rise nor did vascular remodelling occur. Similarly, if Csf1-deficient mice were infused with aldosterone, oxidative stress did not increase and remodelling of the vasculature and endothelial dysfunction were blunted [7]. Interestingly, although the latter appeared to be dependent on innate immune mechanisms, vascular stiffness in response to aldosterone persisted, indicating its independence from innate immunity. This role of macrophage/monocytes and other cells of the innate immune system has been confirmed and extended by Wenzel et al.[8] in very elegant studies in which Ang II was infused into mice expressing the diphtheria toxin receptor in macrophages, which had been ablated by low-dose diphtheria toxin administration. More recently, we have demonstrated that when you cross mice that overexpress human endothelin-1 in the endothelium with Csf-1-deficient mice, they do not develop the typical hypertrophic vascular remodelling or endothelial dysfunction present in endothelin-1 transgenic mice [9]. Thus, Ang II, aldosterone, DOCA, and ET-1 require macrophage/monocytes, cellular elements participating in innate immunity, to exert the totality of their action on the vasculature and other target organs.

Starting with early studies by numerous investigators [10–13], followed by more recent work [14–16], the role of adaptive immunity and T-effector lymphocytes has been demonstrated in rodent models, implicating T-helper (Th)1 and Th17 lymphocytes, and the already mentioned natural killer T lymphocytes. What are these different lymphocyte lineages and how do they develop? IL-12 triggers maturation of naive T lymphocytes towards Th1 cells, which typically produce IFN-γ and IL-2, and are involved in immunity against viruses, intracellular bacteria, and fungi [17]. Th2 lymphocytes produce IL-4, IL-5, and IL-13, and are the defense against parasites. Transforming growth factor (TGF)-β, IL-6, and IL-1, or TGF-β and IL-21 followed by IL-23 commit naive lymphocytes to become Th17 cells that produce IL-17A and F, IL-21 and IL-22 contribute to defense against extracellular bacteria and fungi. Th17 also plays a role in autoimmune diseases. The involvement of effector T lymphocytes in hypertension has now been extended to humans, suggesting for the first time participation of T effector lymphocytes in the pathophysiology of human essential hypertension during aging [18]. Indeed, in human hypertension, with aging, effector lymphocytes may become senescent, and lose some of their CD28 leading to blunting of the CD28:CD80/86 costimulation axis, increased surface adhesion molecules and cytolytic enzyme expression, and enhanced cytotoxicity [18].

Kassan et al. in their review in this issue [1] concentrate on the role of T-regulatory lymphocytes (Treg), which function in homeostatic fashion to oppose the actions of T-effector lymphocytes. These are CD4+ or CD8+ lymphocytes that are also CD25+, and are involved in self-tolerance and maintain immune homeostasis. CD4+ T lymphocytes become Tregs under the influence of transcription factor X-linked forkhead/winged helix (Foxp3) [19]. Tregs mediate their effects via the action of IL-10 or TGF-β that exert anti-inflammatory actions, as well as direct cell–cell contact or via cytotoxic T-lymphocyte antigen-4 [20]. T lymphocytes retain plasticity, and if IL-6 is present in low concentrations, Th17 (proinflammatory) could turn into Treg (protective), for example.

Although perhaps not emphasized in the review of Kassan et al., the cells of the innate and the adaptive system talk to each other through multiple cytokines, and depending on the molecules expressed on their surface, will exert varying actions. An imbalance between the degree of activation of the protective Treg lymphocytes [21–25] and the proinflammatory and cytotoxic macrophages [5–9] and T-effector lymphocytes [14–16] could thus be at the origin of the triggering or not of progression of BP elevation and vascular injury. The ability of the immune system to adapt and exert either protective or deleterious effects is likely to become in the future increasingly complex and offer new surprises, discoveries, and hopefully potential novel targets for intervention that will allow us to improve outcomes in cardiovascular disease.

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ACKNOWLEDGEMENTS

The work of the author was supported by Canadian Institutes of Health Research grants 37917, 82790, and 102606, a Canada Research Chair (CRC) on Hypertension and Vascular Research from the CIHR/Government of Canada CRC Program, and the Canada Fund for Innovation.

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Conflicts of interest

There are no conflicts of interest.

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