T helper subsets regulate inflammatory diseases, including the development of allergic lung inflammation associated with asthma. The development of T helper subsets in controlled by a network of transcription factors that promote the expression of cytokines and other genes associated with the ability of a T helper cell to promote disease. This proposal focuses on the most recently identified subset of T helper cells, Th9 cells that differentiate in response to TGF? and IL-4. Experiments in the proposal will define transcription factors that are important for Th9 cells to promote disease. In the previous funding period we determined a Th9 gene signature and a subset of genes that functionally contribute to the Th9 phenotype. We identified the ETS family member PU.1 as a transcription factor that promotes IL-9 production as it represses Th2 cytokine expression, and that PU.1 expression in T cells is important for the development of allergic inflammation. We defined PU.1 as downstream of the TGF? signal, and demonstrated that IRF4 and BATF are downstream of the IL-4/STAT6 signal. We characterized BATF as a factor important for Th9 development and for allergic inflammation. In the next funding period we will define the function of an ETS family member that might be a lineage-defining factor, and has unique function from PU.1. We will determine how these factors promote IL-9 expression, and also determine how they contribute to the pro-allergic phenotype of Th9 cells. We will further determine the mechanism for the ability of BATF to only promote IL-9 production in Th9 cells, and how BATF contributes to allergic inflammation in T helper cell subsets. Together, the proposed experiments will elucidate a network of transcription factors that regulate IL-9 production and promote a functionally pro-allergic T helper cell subset. Moreover, these studies will define novel contributions of T cells t allergic inflammation and potentially identify new targets for therapeutic intervention.

Public Health Relevance

Allergic inflammation is responsible for a variety of atopic diseases including asthma. We are characterizing a type of T cell that regulates allergic disease. These studies will develop a new understanding of the mechanisms of disease and identify new targets for disease intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI057459-12
Application #
9194372
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Davidson, Wendy F
Project Start
2015-12-11
Project End
2019-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
12
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Koh, Byunghee; Abdul Qayum, Amina; Srivastava, Rajneesh et al. (2018) A conserved enhancer regulates Il9 expression in multiple lineages. Nat Commun 9:4803
Imam, Tanbeena; Park, Sungtae; Kaplan, Mark H et al. (2018) Effector T Helper Cell Subsets in Inflammatory Bowel Diseases. Front Immunol 9:1212
Ulrich, Benjamin J; Verdan, Felipe Fortino; McKenzie, Andrew N J et al. (2017) STAT3 Activation Impairs the Stability of Th9 Cells. J Immunol 198:2302-2309
Ramadan, Abdulraouf; Griesenauer, Brad; Adom, Djamilatou et al. (2017) Specifically differentiated T cell subset promotes tumor immunity over fatal immunity. J Exp Med 214:3577-3596
Kaplan, Mark H (2017) The transcription factor network in Th9 cells. Semin Immunopathol 39:11-20
Rauber, Simon; Luber, Markus; Weber, Stefanie et al. (2017) Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells. Nat Med 23:938-944
Huang, Su; Shen, Yingjia; Pham, Duy et al. (2017) IRF4 Modulates CD8+ T Cell Sensitivity to IL-2 Family Cytokines. Immunohorizons 1:92-100
Olson, Matthew R; Ulrich, Benjamin J; Hummel, Sarah A et al. (2017) Paracrine IL-2 Is Required for Optimal Type 2 Effector Cytokine Production. J Immunol 198:4352-4359
Koh, Byunghee; Hufford, Matthew M; Sun, Xin et al. (2017) Etv5 Regulates IL-10 Production in Th Cells. J Immunol 198:2165-2171
Koh, Byunghee; Hufford, Matthew M; Pham, Duy et al. (2016) The ETS Family Transcription Factors Etv5 and PU.1 Function in Parallel To Promote Th9 Cell Development. J Immunol 197:2465-72

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