Impaired Natural Killer Cell Phenotype and Function in Idiopathic and Heritable Pulmonary Arterial Hypertension
Background—Beyond their role as innate immune effectors, Natural Killer (NK) cells are emerging as important regulators of angiogenesis and vascular remodeling. Pulmonary arterial hypertension (PAH) is characterized by severe pulmonary vascular remodeling and has long been associated with immune dysfunction. Despite this association, a role for NK cells in disease pathology has not yet been described.
Methods and Results—Analysis of whole blood lymphocytes and isolated NK cells from PAH patients revealed an expansion of the functionally defective CD56-/CD16+ NK subset that was not observed in patients with chronic thromboembolic pulmonary hypertension. NK cells from PAH patients also displayed decreased levels of the activating receptor NKp46 and the killer immunoglobulin-like receptors (KIRs) 2DL1/S1 and 3DL1, reduced secretion of the cytokine MIP-1β, and a significant impairment in cytolytic function associated with decreased KIR3DL1 expression. Genotyping patients (n=222) and controls (n=191) for KIR gene polymorphisms did not explain these observations. Rather, we show that NK cells from PAH patients exhibit increased responsiveness to TGF-β, which specifically downregulates disease-associated KIRs. NK cell number and cytotoxicity were similarly decreased in the monocrotaline rat and chronic hypoxia mouse models of PAH, accompanied by reduced production of IFNγ in NK cells from hypoxic mice. NK cells from PAH patients also produced elevated quantities of MMP-9, consistent with a capacity to influence vascular remodeling.
Conclusions—Our work is the first to identify an impairment of NK cells in PAH and suggests a novel and substantive role for innate immunity in the pathobiology of this disease.
- Received April 6, 2012.
- Accepted June 18, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited