Concomitant suppression of TH2 and TH17 cell responses in allergic asthma by targeting retinoic acid receptor-related orphan receptor γt

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:141

Article

Na, Hyeongjin^1,2  Lim, Hoyong¹  Choi, Garam^1,2  Kim, Byung-Keun³  Kim, Sae-Hoon³  Chang, Yoon-Seok³  Nurieva, Roza⁴  Dong, Chen^5,6  Chang, Seon Hee⁴  Chung, Yeonseok^1,2 

[1] Seoul Natl Univ, Lab Immune Regulat, Inst Pharmaceut Sci, Seoul, South Korea

[2] Seoul Natl Univ, Plus Program BK21, Coll Pharm, Seoul, South Korea

[3] Seoul Natl Univ, Coll Med, Div Allergy & Clin Immunol, Dept Internal Med,Seoul Natl Univ Bundang Hosp, Seongnam, South Korea

[4] MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA

[5] Tsinghua Univ, Inst Immunol, Beijing, Peoples R China

[6] Tsinghua Univ, Sch Med, Beijing, Peoples R China

关键词: Allergic asthma;    T(H)17 cell;    T(H)2 cell;    retinoic acid receptor-related orphan receptor gamma t;    B-cell lymphoma 6;   

DOI  :  10.1016/j.jaci.2017.07.050

来源: Elsevier

【 摘 要 】

Background: Allergic asthma is a heterogeneous chronic inflammatory disease of the airways with a massive infiltration of eosinophils or neutrophils mediated by allergen-specific T(H)2 and T(H)17 cells, respectively. Therefore successful treatment of allergic asthma will require suppression of both T(H)2 and T(H)17 cells. Objective: We sought to investigate the role of the T(H)17 cell pathway in regulating T(H)2 cell responses in allergic asthma. Methods: Allergic asthma was induced by intranasal challenge with proteinase allergens in C57BL/6, Il17a 2/2 Il17f 2/2, and retinoic acid receptor-related orphan receptor gt (RORgt) gfp/gfp mice. A pharmacologic RORgt 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 RORgt, exhibited a significant reduction not only in T(H)17 cell responses but also in T(H)2 cell responses in an animal model of allergic asthma. Similarly, mice treated with an RORgt inhibitor had significantly diminished T(H)17 and T(H)2 cell responses, leading to reduced neutrophil and eosinophil numbers in the airway. RORgt-deficient T cells were intrinsically defective in differentiating into T(H)2 cells and expressed increased levels of B-cell lymphoma 6 (Bcl6). Bcl6 knockdown resulted in a remarkable restoration of T(H)2 cell differentiation in RORgtdeficient T cells. Blockade of RORgt also significantly hampered the differentiation of human T(H)2 and T(H)17 cells from naive CD4 1 T cells. Conclusion: RORgt in T cells is required for optimal T(H)2 cell differentiation by suppressing Bcl6 expression; this finding suggests that targeting RORgt might be a promising approach for the treatment of allergic asthma by concomitantly suppressing T(H)17 and T(H)2 cell responses in the airway.

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