Peripheral T-cell remodeling in long-standing PAH: CD4+ reduction and CCR6 enrichment

Introduction

Pulmonary arterial hypertension (PAH) is a complex, progressive disorder characterized by pulmonary vascular remodeling, with inflammation increasingly recognized as an important driver of this process. However, the mechanisms linking these processes remain incompletely understood. The aim of this study was to characterize peripheral blood T-lymphocyte subsets in patients with PAH.

Methods

High-dimensional flow cytometry was employed to profile peripheral T lymphocytes in 23 patients with prevalent PAH and 15 age- and sex-matched healthy controls (HC) (Table 1). A total of 288 T-cell subpopulations were identified and analyzed based on detailed phenotypic and functional markers expression.

Results

The main observations in the PAH group included a significant increase in neutrophil count accompanied by a reduction in total lymphocytes. Within the T-cell compartment, there was a significant decrease in both frequency and absolute counts of CD4+ T cells and CD4−CD8− T cells. Analysis of activation markers across T-cell subpopulations revealed minimal differences between PAH patients and HC, suggesting the lack of overt systemic T cell activation. A remarkable finding was a phenotypic shift toward CCR6-expressing subsets. Specifically, PAH patients exhibited increased proportions of CCR6+ regulatory T cells, CCR5+CCR6+ regulatory T cells, and CCR6+ follicular T cells, indicating enrichment of CCR6-associated profiles (Figure 1).

Assessment of T-cell maturation demonstrated a consistent redistribution toward naïve and effector memory compartments, with a concomitant reduction in central memory subsets. This pattern was observed across multiple CD4+ populations, including regulatory T cells, regulatory follicular T cells, CCR5+ regulatory T cells, and follicular like T cells. Further characterization of memory differentiation revealed an increased proportion of: (a) naïve CD4+CCR5+CCR6+ regulatory T cells; (b) effector memory and effector CD8+ T cells; and (c) effector CD4−CD8− αβ and γδ T cells.

Conclusion

These findings reveal substantial remodeling of the T-lymphocyte compartment in patients with long-standing PAH, characterized by a reduction in CD4+ T cells, redistribution of memory subsets, and enrichment of CCR6-associated profiles. CCR6 is a phenotypic marker of Th17/Tc17 cells, which are typically associated with IL-17 production and the promotion of chronic inflammatory responses. Further studies are needed to elucidate the complex interplay between vascular remodeling and immune dysregulation and to investigate the potential therapeutic role of immunomodulatory interventions in PAH.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.