CD4+ helper T (TH) lymphocytes are essential organizers of adaptive immune responses and key mediators in immune-mediated inflammatory and allergic diseases. Upon activation by antigen-presenting cells (APC), naive TH cells undergo clonal expansion and functional differentiation into cytokine-secreting effector cells. Effector TH cells have been historically classified into TH1 and TH2 subsets. Recently, a novel TH subset, named TH17, that makes IL-17 has been identified by our and other groups. In the last funding cycle, we have investigated the molecular programs governing TH17 differentiation. We have identified key function of STAT3 in mediating cytokine-regulated TH17 differentiation. We further showed that STAT3 is required for upregulation of two TH17-specific orphan nuclear receptors RORa and RORg and that these two factors play synergistic and somewhat redundant function in TH17 differentiation. We also reported that RORa and RORg function in activating the transcription of IL-17 and IL-17F genes, two related cytokine genes but with differential in vivo function, and that the CNS2 element in IL-17-IL-17F gene locus enhances ROR-dependent transcription of IL-17 gene promoter in a reporter assay. Furthermore, we show that Foxp3+ Treg and TH17 cells exhibit antagonistic regulation yet with functional plasticity in vitro and in vivo. Smad2 and Smad3 molecules, both of which are activated by TGFb signaling, differentially regulate Treg and TH17 cell differentiation. Despite these achievements, there are still remaining questions about the transcriptional regulation in TH17 cells. First, are RORs important for maintaining cytokine transcription in mature TH17 cells? Second, how do RORs regulate the transcription of the IL-17 and IL-17F genes? Thirdly, considering RORs associate with various co-activators for their function, what co-activators are required for TH17 cell differentiation? We will pursue these questions in the proposed grant. First, we will determine the function of RORg and RORa in mature TH17 cells and in Treg cells. Secondly, we will examine how RORs regulate TH17 cytokine transcription. We will identify additional elements that may be also required for IL-17F transcription. Lastly, we will genetically analyze the functio of SRC molecules in TH17 differentiation. We will investigate their function and regulation during TH17 cell differentiation in vitro and in vivo. Overall, the proposed project will center on the transcription factors that were shown in the previous cycle to be crucial in TH17 differentiation. We will analyze the biological function of these factors as well as the mechanisms underlying their function. These studies will further substantiate our understanding on these important regulators and facilitate ongoing efforts in targeting these pathways in treatment of human diseases.

Public Health Relevance

Recently, a novel TH subset, named TH17, has been identified to play critical roles in inflammatory diseases. Our proposal is to study the roles of TH17-specific transcription factors RORa and RORg in T cells and the underlying mechanisms. Our work will advance our understanding on these important factors and facilitate ongoing efforts in targeting these pathways in treatment of human diseases.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Cellular and Molecular Immunology - B Study Section (CMIB)
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Mancini, Marie
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University of Texas MD Anderson Cancer Center
Other Domestic Higher Education
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Tanaka, Kentaro; Martinez, Gustavo J; Yan, Xiaowei et al. (2018) Regulation of Pathogenic T Helper 17 Cell Differentiation by Steroid Receptor Coactivator-3. Cell Rep 23:2318-2329
Wang, Xiaohu; Ni, Lu; Chang, Dehui et al. (2017) Cyclic AMP-Responsive Element-Binding Protein (CREB) is Critical in Autoimmunity by Promoting Th17 but Inhibiting Treg Cell Differentiation. EBioMedicine 25:165-174
Kim, Byung-Seok; Lu, Huiping; Ichiyama, Kenji et al. (2017) Generation of ROR?t+ Antigen-Specific T Regulatory 17 Cells from Foxp3+ Precursors in Autoimmunity. Cell Rep 21:195-207
Ichiyama, Kenji; Gonzalez-Martin, Alicia; Kim, Byung-Seok et al. (2016) The MicroRNA-183-96-182 Cluster Promotes T Helper 17 Cell Pathogenicity by Negatively Regulating Transcription Factor Foxo1 Expression. Immunity 44:1284-98
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Ichiyama, Kenji; Chen, Tingting; Wang, Xiaohu et al. (2015) The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells. Immunity 42:613-26
Liu, Xindong; Chen, Xin; Zhong, Bo et al. (2014) Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development. Nature 507:513-8
Wang, Aibo; Pan, Deng; Lee, Young-Hee et al. (2013) Cutting edge: Smad2 and Smad4 regulate TGF-?-mediated Il9 gene expression via EZH2 displacement. J Immunol 191:4908-12
Wang, Xiaohu; Dong, Chen (2013) The CD70-CD27 axis, a new brake in the T helper 17 cell response. Immunity 38:1-3

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