Alterations in circulating helper T-cells in idiopathic pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is characterized by a high pulmonary arterial pressure leading to hypertrophy of the right ventricle (RV) and ultimately death due to RV failure. The most common form of PAH is idiopathic PAH (IPAH) for which no identified risk factor has been found until date. In IPAH, changes in CD4+ T helper (Th)-cell subsets, regulatory Th-cell (Treg) function, and the presence of pulmonary tertiary lymphoid aggregates were observed. We hypothesized that in PAH, Th-cells harbor a proinflammatory phenotype and signs of chronic activation. To investigate this hypothesis, we used a combined cytokine and transcription factor staining on peripheral blood mononuclear cells (PBMCs) from IPAH and healthy controls (HC). The proportion of activated and memory Th-cells were unaltered, however an increase in activated Tregs was observed in IPAH compared to HC. Moreover, activated Th-cells showed an increased expression of inhibitory molecule CTLA-4 and activation marker CD25 in IPAH compared to HC. Strikingly, IPAH Th-cells were less capable of producing IL-6, IFNγ and IL-17 compared to HC. Specifically, RORγt-positive Th17-cells were less qualified to produce IL-17 in IPAH compared to HC. In conclusion, elevated CD25 and CTLA-4 expression on activated Th-cells possibly point at chronic activation leading to an exhausted Th-cell phenotype. The reduced cytokine production can be caused by I) Th-cell exhaustion, II) an increase in activated Tregs, III) homing of cytokine-producing Th-cells towards lungs, or IV) a negative feedback response due to an high cytokine milieu. These Th-cell alterations suggest chronic activation and immune imbalance which could be involved in PAH pathology.