The small molecule inhibitor BX-795 uncouples IL-2 production from inhibition of Th2 inflammation and induces CD4+ T cells resembling iTreg

Frontiers in Immunology

Immunology

Sophia Derdak¹  Gabriele Gadermaier²  Thomas Brocker³  Lisa Rausch³  Jan Kranich³  Hannes Stockinger⁴  Philipp Schatzlmaier⁴  Doris Trapin⁵  Sabrina Jutz⁵  Maja Zabel⁵  Peter A. Tauber⁵  Cordula Köhler⁵  Bernhard Kratzer⁵  Peter Steinberger⁵  Ursula Smole⁵  Alina Neunkirchner⁵  Winfried F. Pickl⁶ 

[1] Core Facilities, Medical University of Vienna, Vienna, Austria;Department of Biosciences, University of Salzburg, Salzburg, Austria;Institute for Immunology, Biomedical Center (BMC), Faculty of Medicine, Ludwig Maximilian University (LMU) Munich, Munich, Germany;Institute of Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria;Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria;Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria;Karl Landsteiner University of Healthcare, Krems, Austria;

关键词: Immunomodulation;    IL-2;    regulatory T cells;    small molecule inhibitor;    allergy;    Th2 cells;   

DOI  :  10.3389/fimmu.2023.1094694

 received in 2022-11-10, accepted in 2023-03-06,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundTreg cells have been shown to be an important part of immune-homeostasis and IL-2 which is produced upon T cell receptor (TCR)-dependent activation of T lymphocytes has been demonstrated to critically participate in Treg development.ObjectiveTo evaluate small molecule inhibitors (SMI) for the identification of novel IL-2/Treg enhancing compounds.Materials and methodsWe used TCR-dependent and allergen-specific cytokine secretion of human and mouse T cells, next generation messenger ribonucleic acid sequencing (RNA-Seq) and two different models of allergic airway inflammation to examine lead SMI-compounds.ResultsWe show here that the reported 3-phosphoinositide dependent kinase-1 (PDK1) SMI BX-795 increased IL-2 in culture supernatants of Jurkat E6-1 T cells, human peripheral blood mononuclear cells (hPBMC) and allergen-specific mouse T cells upon TCR-dependent and allergen-specific stimulation while concomitantly inhibiting Th2 cytokine secretion. RNA-Seq revealed that the presence of BX-795 during allergen-specific activation of T cells induces a bona fide Treg cell type highly similar to iTreg but lacking Foxp3 expression. When applied in mugwort pollen and house dust mite extract-based models of airway inflammation, BX-795 significantly inhibited Th2 inflammation including expression of Th2 signature transcription factors and cytokines and influx into the lungs of type 2-associated inflammatory cells such as eosinophils.ConclusionsBX-795 potently uncouples IL-2 production from Th2 inflammation and induces Th-IL-2 cells, which highly resemble induced (i)Tregs. Thus, BX-795 may be a useful new compound for the treatment of allergic diseases.

【 授权许可】

Unknown   
Copyright © 2023 Tauber, Kratzer, Schatzlmaier, Smole, Köhler, Rausch, Kranich, Trapin, Neunkirchner, Zabel, Jutz, Steinberger, Gadermaier, Brocker, Stockinger, Derdak and Pickl