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IL ‐2‐related regulatory CD4 T‐cell deficiency leads to the development of lung fibrosis and vascular remodeling

Abstract : Objectives: Systemic sclerosis (SSc) is a dreadful autoimmune disease characterized by severe lung outcomes reducing life expectancy. Fra2TG mice offer the opportunity to decipher the relationships between the immune system and lung fibrosis. We herein investigated whether Fra2TG mice lung phenotype could result from an imbalance between the effector and the regulatory arms of the CD4 T-cell compartment. Methods: The homeostasis and phenotype of peripheral CD4 T cells from Fra2TG and control mice were first extensively characterized by multicolor flow cytometry. Then, different cures aimed at restoring regulatory CD4 T-cell (Treg) homeostasis have been tested, including adoptive transfer of Treg cells and treatment with low-dose IL-2. Results: Fra2TG mice exhibited a marked decrease in the proportion and absolute number of peripheral Treg cells which precedes the accumulation of activated, TH 2-polarized, CD4 T cells. This defect in Treg-cell homeostasis derived from combined mechanisms including an impaired generation of these cells in both the thymus and the periphery. The impaired ability of peripheral conventional CD4 T cells to produce IL-2 may greatly participate to Treg-cell deficiency in Fra2TG mice. Remarkably, adoptive transfer of Tregs, low-dose IL-2 therapy or combination of both all corrected the phenotype of Fra2TG mice, with a significant reduction in pulmonary parenchymal fibrosis and lung vascular remodeling. Conclusion: Immunotherapies aiming at restoring Treg-cell homeostasis could be relevant in SSc. An intervention based on low-dose IL-2 injections, as already proposed in other autoimmune diseases, could be the most suitable modality for future developments.
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https://www.hal.inserm.fr/inserm-03652770
Contributor : Christophe Guignabert Connect in order to contact the contributor
Submitted on : Wednesday, April 27, 2022 - 9:19:21 AM
Last modification on : Friday, August 5, 2022 - 11:56:40 AM
Long-term archiving on: : Friday, July 29, 2022 - 9:11:53 AM

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Camelia Frantz, Anne Cauvet, Aurélie Durand, Virginie Gonzalez, Rémi Pierre, et al.. IL ‐2‐related regulatory CD4 T‐cell deficiency leads to the development of lung fibrosis and vascular remodeling. Arthritis & rheumatology, Wiley, 2022, Online ahead of print. ⟨10.1002/art.42111⟩. ⟨inserm-03652770⟩

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