T-Helper 17 Cell Polarization in Pulmonary Arterial Hypertension

doi:10.1378/chest.14-1678

Chest

Volume 147, Issue 6, June 2015, Pages 1610-1620

https://doi.org/10.1378/chest.14-1678 Get rights and content

BACKGROUND

Inflammation may contribute to the pathobiology of pulmonary arterial hypertension (PAH). Deciphering the PAH fingerprint on the inflammation orchestrated by dendritic cells (DCs) and T cells, key driver and effector cells, respectively, of the immune system, may allow the identification of immunopathologic approaches to PAH management.

METHODS

Using flow cytometry, we performed immunophenotyping of monocyte-derived DCs (MoDCs) and circulating lymphocytes from patients with idiopathic PAH and control subjects. With the same technique, we performed cytokine profiling of both populations following stimulation, coculture, or both. We tested the immunomodulatory effects of a glucocorticoid (dexamethasone [Dex]) on this immunophenotype and cytokine profile. Using an epigenetic approach, we confirmed the immune polarization in blood DNA of patients with PAH.

RESULTS

The profile of membrane costimulatory molecules of PAH MoDCs was similar to that of control subjects. However, PAH MoDCs retained higher levels of the T-cell activating molecules CD86 and CD40 after Dex pretreatment than did control MoDCs. This was associated with an increased expression of IL-12p40 and a reduced migration toward chemokine (C-C motif) ligand 21. Moreover, both with and without Dex, PAH MoDCs induced a higher activation and proliferation of CD4⁺ T cells, associated with a reduced expression of IL-4 (T helper 2 response) and a higher expression of IL-17 (T helper 17 response). Purified PAH CD4⁺ T cells expressed a higher level of IL-17 after activation than did those of control subjects. Lastly, there was significant hypomethylation of the IL-17 promoter in the PAH blood DNA as compared with the control blood.

CONCLUSIONS

We have highlighted T helper 17 cell immune polarization in patients with PAH, as has been previously demonstrated in other chronic inflammatory and autoimmune conditions.

Section snippets

Collection of Blood Samples

All patients and control subjects studied were part of the French Network on Pulmonary Hypertension, a program approved by our institutional ethics committee, and gave written informed consent:

•
Protocol No: CO-08-003, ID Recherches et Collections Biologiques: 2008-A00485-50
•
Principal investigator: Marc Humbert, MD, PhD
•
CPP (Comité de protection des personnes) de Bicêtre (CPP IDF VII).

Subjects were > 18 years of age and patients with iPAH or hPAH (BMPR2 mutation carriers) had a diagnosis

Differences in iPAH MoDCs Sensitivity to Dex

After differentiation of monocytes into DCs, MoDCs were primed with IFN-γ (10 ng/mL) with or without Dex (10⁻⁶ M). The primed cells were then activated with lipopolysaccharide (1 μg/mL). The phenotype of MoDCs was characterized by the analysis of a range of DC markers by flow cytometry: CD80, CD86, CD40, MHC-II, CD11c, CD209, B7H1, B7H2, and ILT3. As expected, Dex decreased the expression of activation markers on MoDCs such as CD40, CD80, and CD86, and maintained a higher expression of markers

Discussion

We have demonstrated that under similar differentiation and activation conditions, iPAH MoDCs exhibit a profile of membrane costimulatory molecules similar to that of control MoDCs. As expected, GC (Dex) decreased the activation of MoDCs. However, PAH MoDCs retained a higher level of the T cell-activating molecules CD86 and CD40 after Dex pretreatment than did control MoDCs. This was associated with an increased expression of p40 (IL-12 and IL-23 subunit) and a reduced migration toward CCL21.

Conclusions

In conclusion, the dysregulated immune response associated with iPAH or hPAH may be related in part to DC dysfunction and to increased Th17 immune polarization. Indeed, this polarization has been shown to be involved in several chronic inflammatory and autoimmune conditions, but not previously in PAH.

Acknowledgments

Author contributions: F. P. is the guarantor of this manuscript and takes responsibility for its content, including the data and analysis. A. H., B. G., D. M., S. C.-K., L. P., B. N. L., M. H., and F. P. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects; and A. H., B. G., D. M., S. C.-K., L. P., B. N. L., M. H., and F. P. contributed to the study design, the data

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FUNDING/SUPPORT: Ms Hautefort is supported by a PhD grant from Région Ile de France (CORDDIM). This study was supported by grants from the National Funding Agency for Research (ANR) [Grant ANR-13-JSV1-001] and from the Fondation pour la Recherche Médicale (FRM) [EQ20100318257].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

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Chest

Original Research: Pulmonary Vascular DiseaseT-Helper 17 Cell Polarization in Pulmonary Arterial Hypertension

BACKGROUND

METHODS

RESULTS

CONCLUSIONS

Section snippets

Collection of Blood Samples

Differences in iPAH MoDCs Sensitivity to Dex

Discussion

Conclusions

Acknowledgments

Chest

Drug Discov Today

Chest

Drug Discov Today

Lancet

J Autoimmun

Trends Immunol

Trends Immunol

Drug Discov Today

Treatment of pulmonary arterial hypertension

N Engl J Med

Immune dysregulation and endothelial dysfunction in pulmonary arterial hypertension: a complex interplay

Circulation

Progress in pulmonary arterial hypertension pathology: relighting a torch inside the tunnel

Am J Respir Crit Care Med

The role of inflammation and autoimmunity in the pathophysiology of pulmonary arterial hypertension

Clin Rev Allergy Immunol

Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure

Am J Physiol Lung Cell Mol Physiol

Inflammation, endothelial injury, and persistent pulmonary hypertension in heterozygous BMPR2-mutant mice

Am J Physiol Heart Circ Physiol

Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension

Am J Respir Crit Care Med

Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension

Circulation

Leptin and regulatory T-lymphocytes in idiopathic pulmonary arterial hypertension

Eur Respir J

Proinflammatory cytokine levels are linked to death in pulmonary arterial hypertension

Eur Respir J

Nuclear factor κ-B is activated in the pulmonary vessels of patients with end-stage idiopathic pulmonary arterial hypertension

PLoS ONE

Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension

Am J Respir Crit Care Med

Prednisolone ameliorates idiopathic pulmonary arterial hypertension

Am J Respir Crit Care Med

Original Research: Pulmonary Vascular Disease
T-Helper 17 Cell Polarization in Pulmonary Arterial Hypertension