Regulatory T Cells Limit Vascular Endothelial Injury and Prevent Pulmonary Hypertension

Abstract

Rationale Pulmonary arterial hypertension (PAH) is an incurable disease associated with viral infections and connective tissue diseases. The relationship between inflammation and disease pathogenesis in these disorders remains poorly understood. Objective To determine whether immune dysregulation due to absent T cell populations directly contributes to the development of PAH. Methods and Results Vascular endothelial growth factor receptor 2 (VEGFR2) blockade induced significant pulmonary endothelial apoptosis in T-cell deficient rats but not in immune-reconstituted (IR) rats. T cell-lymphopenia in association with VEGFR2 blockade resulted in periarteriolar inflammation with macrophages, and B cells even prior to vascular remodeling and elevated pulmonary pressures. IR prevented early inflammation and attenuated PAH development. IR with either CD8 T cells alone or with CD4-depleted spleen cells was ineffective in preventing PAH whereas CD4-depleting immunocompetent euthymic animals increased PAH susceptibility. IR with either CD4+CD25hi or CD4+CD25- T cell subsets prior to vascular injury attenuated the development of PAH. Immune reconstitution limited perivascular inflammation and endothelial apoptosis in rat lungs in association with increased FoxP3+-, IL-10- and TGF-β– expressing CD4 cells, and upregulation of pulmonary bone morphogenetic protein receptor type 2 (BMPR2)-expressing cells, a receptor that activates endothelial cell survival pathways. Conclusions PAH may arise when regulatory T cell (Treg) activity fails to control endothelial injury. These studies suggest that regulatory T cells normally function to limit vascular injury and may protect against the development of PAH.

Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

“…Furthermore, pulmonary vascular remodelling can occur in response to inflammatory cytokines [53]. In an experimental model of PH, inflammation associated with CD4 immunodeficiency may be a predisposing factor for PH development [94]. In support of this, patients with certain PAH-associated conditions, e.g.…”

“…systemic sclerosis, HIV infection and systemic lupus erythematosus, have previously been shown to exhibit abnormalities in T-regulatory cell number and function [54][55][56]. This may render these patients more susceptible to pulmonary vascular inflammation and remodelling after initial vascular injury [94]. However, the exact nature of inflammation as a cause or effect is still unknown in IPAH.…”

Leptin and regulatory T-lymphocytes in idiopathic pulmonary arterial hypertension

“…Although the pathophysiology of IPAH has been extensively studied in the past few decades and several new pathways have been identified, the aetiology of this disease is still not clearly understood. It is now well established that inflammation plays an important role in IPAH [2][3][4][5][6], and increasing data also support the hypothesis that immunological disorders could be present in IPAH patients: circulating autoantibodies have been detected [7,8] and recent evidence indicates that regulatory T-cells (Tregs) could play a role in pulmonary arterial hypertension (PAH) [9]. Despite these findings, little is known about the exact role of inflammation and dysimmunity in the development of IPAH and it remains unclear how immune mechanisms contribute to the pathogenesis of IPAH.…”

Hypertension artérielle pulmonaire

“…Il a été récem-ment démontré que le blocage du récepteur du VEGF (vascular endothelial growth factor) (VEGFR2) induit une apoptose significative des cellules endothéliales pulmonaires chez les rats déficients en cellules T, mais pas chez ces rats après une reconstitution immunitaire. Des transferts de cellules Treg avant induction de l'agression endothéliale suggèrent que les Treg fonctionnent en limitant l'agression endothéliale, et pourraient jouer un rôle protecteur vis-à-vis du déve-loppement de l'HTAP, en plus de leur action régulatrice éventuelle d'une réponse auto-immune [27]. Il est intéressant de noter que la voie BMPR-II qui est altérée au cours de l'HTAP héritable, mais aussi dans d'autres formes de la maladie, joue un rôle dans le développement des cellules T dans le thymus [16], ce qui pourrait contribuer à un défaut intrinsèque de la fonction et/ou du nombre de Treg chez les patients souffrant d'HTAP.…”

“…• Prédominance féminine [4,12,14] • Association entre maladies inflammatoires, infectieuses et autoimmunes avec l'HTAP • Défaut de cellules T régulatrices [16,[23][24][25][26][27][28] • Présence d'auto-anticorps circulants [8-10, 29-33, 37, 40] • Rôle physiopathologique des auto-anticorps in vitro [30,31] • Néogenèse lymphoïde périvasculaire : follicules tertiaires pulmonaires [17] • Dépôts d'Ig dans les lésions vasculaires [16,17] • Transfert de la maladie de l'animal malade à l'animal sain [39] Étapes décisives restant à explorer …”