Dynamic control of Th2 cell responses by STAT3 during allergic lung inflammation in mice Hoyong Lim 1 , Minkyoung Cho 1 , Garam Choi, Hyeongjin Na, Yeonseok Chung ⁎ Laboratory of Immune Regulation, Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea abstract article info Article history: Received 21 February 2015 Accepted 28 March 2015 Available online xxxx Keywords: STAT3 Allergic asthma Th2 cell Th17 cell Th1 cell Signal transducer and activator of transcription (STAT) family molecules play essential roles during the differen- tiation of helper T cells from naïve precursors. Although the role of STAT3 in driving Th17 cell polarization has been well established, its role on Th2 responses to allergens remains incompletely understood. By employing T cell-specific STAT3 deficient mice, we demonstrate that STAT3 in T cells plays diverse role on Th2 cells depending on their locations in an animal model of allergic asthma. In the bronchial lymph nodes, STAT3-deficient T cells produced significantly reduced levels of Th2 cytokines. The frequencies of Th2 cells among CD4 + T cells in the lung were comparable between STAT3-sufficient and STAT3-deficient T cells. By contrast, STAT3-deficient T cells in the airway exhibited significantly enhanced production of Th2 cell cytokines compared to STAT3- sufficient T cells. Interestingly, a major population of IL-4/5 producers among STAT3-deficient T cells in the air- way co-produced IFNγ. The frequency of Th17 cells was significantly diminished whereas that of Th1 cells was increased in all the lung-associated tissues. Our results demonstrate the dynamic and opposing roles of STAT3 during the development of Th2 cells from bronchial lymph nodes to the airway and propose the need of careful consideration on STAT3-targeting approaches for the treatment of lung diseases. © 2015 Elsevier B.V. All rights reserved. 1. Introduction Allergic asthma is a heterogeneous inflammatory disease of the lung characterized by airway hyper-reactivity, mucus hyperplasia, remodel- ing of airway, and symptoms of recurrent wheezing and shortness of breath resulting from intermittent airway obstruction [1–5]. These pathological features are commonly attributed to activities of allergen specific helper T cell responses via the recruitment of inflammatory cells into the airway including eosinophils and neutrophils [1,2,6,7]. It has been well documented that Th2 cells mediate eosinophilic asthma while Th17 cells drive neutrophilic asthma by producing IL-5 and IL-17, respectively [6,8–14]. One of the most commonly used med- ications for asthma in humans is steroid due to its anti-inflammatory and immunosuppressive effects [15–18]. In particular, inhaled corti- coids are found to be effective in controlling Th2 cell-driven eosinophilic asthma [19–21]. However, long term use of steroid can result in a num- ber of side effects including fungal infection in the airway. Moreover, recent studies revealed that neutrophilic asthma is resistant to cortico- steroid [21–25]. Therefore there is an urgent need to develop a thera- peutic intervention for the treatment of asthma. In this regard, a number of approaches have been performed in order to inhibit Th2 pathway by blocking Th2 cytokines or their receptors in experimental animals and in humans [26–29]. So far, however, targeting Th2 immuni- ty in clinical setting has been disappointing [25,30]. More recently, monoclonal antibodies against IL-17 or IL-17RA have been clinically tested in asthmatic patients with corticoid-resistant asthma, and found to have limited effects in controlling clinical symptoms [31,32]. Notably, these antibodies were proven to be effective in controlling other Th17 cell-mediated immune disorders such as psoriasis [21,33]. Hence blockade of either Th2 or Th17 cell response is likely not suffi- cient to suppress ongoing asthma. A novel subset of helper T cells producing both IL-17 and IL-4 has been found in patients with chronic severe asthma [5,34]. Memory and effector T cells co-expressing the transcription factors GATA3 and RORγt and co-producing Th17 and Th2 cytokines have been reported in mice [35]. It will be important to test whether targeting Th2 and Th17 cell pathways simultaneously can ameliorate the symptoms of T cell-mediated allergic asthma. After stimulation with their cognate antigens, CD4 + T cells can be differentiated into diverse effector subsets. Activation of STAT molecules by innate cytokines is essential for the differentiation of helper T cell subsets; STAT4, 6, 3 and 5 are indispensable for the polarization of Th1, 2, 17 and regulatory T cells from naïve T cells, respectively [1, 36–46]. Interestingly, a few recent studies proposed that STAT3 is also required for optimal Th2 cell differentiation through its binding to Th2 cell associated gene loci as well as via enhancing STAT6 activity in T cells [37,47]. International Immunopharmacology xxx (2015) xxx–xxx ⁎ Corresponding author. E-mail address: yeonseok@snu.ac.kr (Y. Chung). 1 These authors contributed equally to this work. INTIMP-03634; No of Pages 8 http://dx.doi.org/10.1016/j.intimp.2015.03.051 1567-5769/© 2015 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp Please cite this article as: H. Lim, et al., Dynamic control of Th2 cell responses by STAT3 during allergic lung inflammation in mice, Int Immunopharmacol (2015), http://dx.doi.org/10.1016/j.intimp.2015.03.051