Concomitant suppression of T_H2 and T_H17 cell responses in allergic asthma by targeting retinoic acid receptor-related orphan receptor γt.

Abstract

Allergic asthma is a heterogeneous chronic inflammatory disease of the airways with a massive infiltration of eosinophils or neutrophils mediated by allergen-specific T_H2 and T_H17 cells, respectively. Therefore successful treatment of allergic asthma will require suppression of both T_H2 and T_H17 cells. We sought to investigate the role of the T_H17 cell pathway in regulating T_H2 cell responses in allergic asthma. Allergic asthma was induced by intranasal challenge with proteinase allergens in C57BL/6, Il17a^-/-Il17f^-/-, and retinoic acid receptor-related orphan receptor γt (RORγt)^gfp/gfp mice. A pharmacologic RORγt inhibitor was used to evaluate its preventive and therapeutic effects in allergic asthma. Characteristics of allergic airway inflammation were analyzed by using flow cytometry, histology, quantitative real-time PCR, and ELISA. Mixed bone marrow chimeric mice, fate mapping analysis, short hairpin RNA transduction, and in vitro T-cell differentiation were used for mechanistic studies. Mice deficient in IL-17A and IL-17F, as well as RORγt, exhibited a significant reduction not only in T_H17 cell responses but also in T_H2 cell responses in an animal model of allergic asthma. Similarly, mice treated with an RORγt inhibitor had significantly diminished T_H17 and T_H2 cell responses, leading to reduced neutrophil and eosinophil numbers in the airway. RORγt-deficient T cells were intrinsically defective in differentiating into T_H2 cells and expressed increased levels of B-cell lymphoma 6 (Bcl6). Bcl6 knockdown resulted in a remarkable restoration of T_H2 cell differentiation in RORγt-deficient T cells. Blockade of RORγt also significantly hampered the differentiation of human T_H2 and T_H17 cells from naive CD4⁺ T cells. RORγt in T cells is required for optimal T_H2 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 T_H17 and T_H2 cell responses in the airway.