The Role of Regulatory T Cells in Pulmonary Arterial Hypertension

P ulmonary arterial hypertension (PAH) is a life-threatening disease with poor prognosis. As a subtype of pulmonary hypertension, PAH results from various etiologies. Accordingly, it is mainly divided into idiopathic PAH, heritable PAH, drugand toxin-induced PAH, and PAH associated with connective tissue diseases; portal hypertension; HIV infection; congenital heart disease; and schistosomiasis. PAH is characterized by vascular lumen narrowing attributable to pulmonary vascular remodeling, which leads to increased pulmonary arterial pressure. In detail, excessive and persistent pulmonary vasoconstriction results from various factors, stimulating increased pulmonary arterial pressure. Furthermore, irreversible vascular remodeling, including pulmonary artery endothelial cell (PAEC) dysfunction, abnormal proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs), extravagant fibroblast proliferation and activation, and immune dysfunction are the main driving factors in PAH progression. Together with structural remodeling, pulmonary vascular dysfunction aggravates PAH progression and eventually leads to heart failure and death. The pathophysiological mechanisms of PAH are complex, involving immunological abnormality and inflammation. Recently, it was demonstrated that T cells play a critical role in pulmonary vascular remodeling and the development of PAH. Tamosiuniene et al suggested that athymic nude rats lacking mature T cells developed more severe pulmonary hypertension than immune-reconstituted rats, which indicated that T lymphocytes attenuate early inflammation following Sugen 5416–induced vascular injury in a rat model and subsequently protect against the development of PAH. However, the T-lymphocyte subsets, which include helper T cells (Th cells), cytotoxic T cells, and regulatory T cells (Tregs), play different roles in PAH. Among the helper T-cell subtypes, exploration has shown that Th1 and Th17 cells widely cause the inflammatory and autoimmune responses in PAH by producing interleukin-6, interleukin-2, interleukin-21, interferon-c, and tumor necrosis factor-a. It has been directly demonstrated that Th17 cells promote the course of PAH in hypoxia-induced rats via the secretion of interleukin-17A, while inhibition of Th17 cells significantly attenuated the increased pressure and remodeling response to chronic hypoxia. In addition, it has been verified that Th2 cells exacerbate PAH progression. Inhibition of Th2 cells by chemoattractant receptor homologous molecule expressed on Th2 cells could suppress interleukin-4 and interleukin-13 secretion to reduce inflammation and thereby alleviate the elevated right ventricular systolic pressure and pulmonary vascular remodeling in rodent PAH models. Moreover, Austin et al found that patients with idiopathic PAH and heritable PAH had abnormally increased cytotoxic T cells in the peripheral lung tissue, and identified that cytotoxic T cells promote the development of PAH via its potent cytolytic activity to trigger the local inflammatory response. In contrast, Tregs were recently found to contribute to immunosuppressive progress and further ameliorate PAH by regulating pulmonary vascular wall inflammation and inhibiting pulmonary artery remodeling. The Treg population and the subtype ratio of T lymphocytes can be considered a critical biomarker of PAH prognosis. Under interleukin-12, interleukin-4, interleukin-6, interleukin10, and transforming growth factor-b (TGF-b) stimulation, T lymphocytes could differentiate into different subsets including Th1, Th2, Th17, and Tregs, with relative balanced quantities in normal physiological homeostasis. Conversely, disproportion of these subsets, especially reduced Tregs and increased Th17 cells, also described as Treg/Th17 ratio imbalance, may lead to significant perturbations of the immune response, thereby affecting the natural progression of PAH. Furthermore, disproportionate Treg/Th17 ratios have been reported in various PAH, especially in idiopathic PAH, heritable PAH, and PAH associated with connective tissue diseases, which has been identified as positively correlated with PAH severity and prognosis. From the Department of Cardiovascular Medicine, The Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, Zhuzhou, Hunan, China. Correspondence to: Yuan Guo, MD, PhD, 116 South Changjiang Road, Department of Cardiovascular Medicine, The Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, Zhuzhou, Hunan 412000, China. E-mail: guoyuan8141@csu.edu. cn J Am Heart Assoc. 2019;8:e014201. DOI: 10.1161/JAHA.119. 014201. a 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.