Evidence for a Role of CCR6+ T Cells in Chronic Thromboembolic Pulmonary Hypertension

Abstract

Introduction: Previous studies have shown an increase of T cells and chemokines in vascular lesions of patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, detailed characterization of these T cells is still lacking, nor have treatment effects been evaluated.

Methods: We included 41 treatment-naive CTEPH patients at diagnosis, 22 patients at 1-year follow-up, and 17 healthy controls (HCs). Peripheral blood T cells were characterized by flow cytometry for subset distribution, cytokine expression and activation marker profile. We used multiplex immunofluorescence to identify CCR6⁺ T cells in endarterectomy tissue from 25 patients.

Results: At diagnosis, proportions of CCR6⁺ CD4⁺ T cells were increased in CTEPH patients compared with HCs. Patients displayed a significantly reduced production capacity of several cytokines including TNFα, IFNγ, GM-CSF and IL-4 in CD4⁺ T cells, and TNFα and IFNγ in CD8⁺ T cells. CD4⁺ and CD8⁺ T cells showed increased expression of the immune checkpoint protein CTLA4. Multivariate analysis separated CTEPH patients from HCs, based on CCR6 and CTLA4 expression. At 1-year follow-up, proportions of CCR6⁺CD4⁺ T cells were further increased, IFNγ and IL-17 production capacity of CD4⁺ T cells was restored. In nearly all vascular lesions we found substantial numbers of CCR6⁺ T cells.

Conclusion: The observed increase of CCR6⁺ T cells and modulation of the IFNγ and IL-17 production capacity of circulating CD4⁺ T cells at diagnosis and 1-year follow-up - together with the presence of CCR6⁺ T cells in vascular lesions - support the involvement of the Th17-associated CCR6⁺ T cell subset in CTEPH.

Keywords: CCR6; CTLA4; T cell; chronic thromboembolic pulmonary hypertension; cytokine; immunology.