Regulatory T Cell Dysfunction in Idiopathic, Heritable and Connective Tissue-Associated Pulmonary Arterial Hypertension

BACKGROUND: Pulmonary arterial hypertension (PAH) encompasses a group of conditions with distinct causes. Immunologic disorders are common features of all forms of PAH and contributes to both disease susceptibility and progression. Regulatory T lymphocytes (Treg) are dysfunctional in patients with idiopathic PAH (iPAH) in a leptin-dependent manner. However, it is not known whether these abnormalities are specific to iPAH. Hence, we hypothesized that (1) Treg dysfunction is also present in heritable (hPAH) and connective tissue disease-associated PAH (CTD-PAH); (2) defective leptin-dependent signaling is present in hPAH and CTD-PAH and could contribute to Treg dysfunction; (3) modulating the leptin axis in vivo could protect against Treg dysfunction; and (4) restoration of Treg activity could limit or reverse experimental chronic hypoxia-induced pulmonary hypertension in vivo. METHODS: We analyzed 62 patients with PAH (30 with iPAH, 18 with hPAH, and 14 with CTD-PAH), 7 patients with CTD without PAH, and 20 healthy control subjects. RESULTS: Our results indicate that Treg are dysfunctional in all PAH forms tested, as well as in patients with CTD without PAH. Importantly, the leptin axis is crucial in Treg dysfunction in patients with iPAH and those with CTD (with or without PAH), whereas in patients with hPAH, Treg are altered in a leptin-independent manner. We found that leptin receptor-deficient rats, which develop less severe hypoxia-induced pulmonary hypertension, are protected against decreased Treg function after hypoxic exposure. CONCLUSIONS: Taken together, our results suggest that Treg dysfunction is common to all forms of PAH and may contribute to the development and the progression of the disease.