Concomitant suppression of T H 2 and T H 17 cell responses in allergic asthma by targeting retinoic acid receptor-related orphan receptor γt.

BACKGROUND: Allergic asthma is a heterogeneous chronic inflammatory disease of the airways with a massive infiltration of eosinophils or neutrophils mediated by allergen-specific TH 2 and TH 17 cells, respectively. Therefore successful treatment of allergic asthma will require suppression of both TH 2 and TH 17 cells.

OBJECTIVE: We sought to investigate the role of the TH 17 cell pathway in regulating TH 2 cell responses in allergic asthma.

METHODS: 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.

RESULTS: Mice deficient in IL-17A and IL-17F, as well as RORγt, exhibited a significant reduction not only in TH 17 cell responses but also in TH 2 cell responses in an animal model of allergic asthma. Similarly, mice treated with an RORγt inhibitor had significantly diminished TH 17 and TH 2 cell responses, leading to reduced neutrophil and eosinophil numbers in the airway. RORγt-deficient T cells were intrinsically defective in differentiating into TH 2 cells and expressed increased levels of B-cell lymphoma 6 (Bcl6). Bcl6 knockdown resulted in a remarkable restoration of TH 2 cell differentiation in RORγt-deficient T cells. Blockade of RORγt also significantly hampered the differentiation of human TH 2 and TH 17 cells from naive CD4+ T cells.

CONCLUSION: RORγt in T cells is required for optimal TH 2 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 TH 17 and TH 2 cell responses in the airway.