Concomitant suppression of Th2 and Th17 cell responses in allergic asthma by targeting RORγt

Publication date: Available online 22 September 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Hyeongjin Na, Hoyong Lim, Garam Choi, Byung Keun Kim, Sae-Hoon Kim, Yoon-Seok Chang, Roza Nurieva, Chen Dong, Seon Hee Chang, Yeonseok Chung
BackgroundAllergic asthma is a heterogeneous chronic inflammatory disease in the airway with a massive infiltration of eosinophils or neutrophils mediated by allergen-specific Th2 cells and Th17 cells, respectively. Successful treatment of allergic asthma will therefore require suppression of both Th2 and Th17 cells.ObjectiveWe sought to investigate the role of Th17 cell pathway in regulating Th2 cell responses in allergic asthma.MethodsAllergic asthma was induced by intranasal challenges with proteinase allergens in C57BL/6, Il17a−/−Il17f− /−and RORγt^gfp/gfp mice. Pharmacological RORγt inhibitor was used to evaluate its preventive and therapeutic effects in allergic asthma. Characteristics of allergic airway inflammation were analyzed by flow cytometry, histology, qRT-PCR and ELISA. Mixed bone marrow chimeric mice, fate mapping analysis, shRNA transduction and in vitro T cell differentiation were employed for mechanistic studies.ResultsMice deficient in IL-17A and IL-17F as well as in RORγt exhibited a significant reduction not only in Th17 cell responses, but also in Th2 cell responses in an animal model of allergic asthma. Similarly, mice treated with an RORγt inhibitor showed significantly diminished Th17 as well as Th2 cell responses, leading to reduced numbers of neutrophils and eosinophils in the airway. RORγt-deficient T cells were intrinsically defective in differentiating into Th2 cells and expressed increased level of Bcl6. Knock-down of Bcl6 resulted in a remarkable restoration of Th2 cell differentiation in RORγt-deficient T cells. Blockade of RORγt also significantly hampered the differentiation of human Th2 cells and Th17 cells from naïve CD4⁺ T cells.ConclusionRORγt in T cells is required for optimal Th2 cell differentiation by suppressing Bcl6 expression; this finding suggests that targeting RORγt might be a promising approach for the treatment of allergic asthma by concomitantly suppressing Th17 and Th2 cell responses in the airway.

Teaser

Inhibition of RORγt suppresses both Th2 and Th17 cell responses in the airway, and this can become a potential therapeutic target for the treatment of allergic asthma.


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