Central role of T helper 17 cells in chronic hypoxia-induced pulmonary hypertension

Inflammation is a prominent pathological feature in<br>pulmonary arterial hypertension, as demonstrated by pulmonary vascular infiltration of inflammatory cells, including T and B lymphocytes.<br>However, the contribution of the adaptive immune system is not well characterized in pulmonary hypertension caused by chronic hypoxia. CD4 T cells are required for initiating and maintaining inflammation, suggesting that these cells could play an important role<br>in the pathogenesis of hypoxic pulmonary hypertension. Our objective was to test the hypothesis that CD4 T cells, specifically the T helper 17 subset, contribute to chronic hypoxia-induced pulmonary hypertension.<br>We compared indices of pulmonary hypertension resulting from chronic hypoxia (3 wk) in wild-type mice and recombination–activating gene 1 knockout mice (RAG1/, lacking mature T and B cells). Separate sets of mice were adoptively transferred with CD4,<br>CD8, or T helper 17 cells before normoxic or chronic hypoxic<br>exposure to evaluate the involvement of specific T cell subsets.<br>RAG1/ mice had diminished right ventricular systolic pressure and<br>arterial remodeling compared with wild-type mice exposed to chronic<br>hypoxia. Adoptive transfer of CD4 but not CD8 T cells<br>restored the hypertensive phenotype in RAG1/ mice. Interestingly,<br>RAG1/ mice receiving T helper 17 cells displayed evidence of<br>pulmonary hypertension independent of chronic hypoxia. Supporting<br>our hypothesis, depletion of CD4 cells or treatment with SR1001, an<br>inhibitor of T helper 17 cell development, prevented increased pressure<br>and remodeling responses to chronic hypoxia. We conclude that<br>T helper 17 cells play a key role in the development of chronic<br>hypoxia-induced pulmonary hypertension.