CD4+ helper T (TH) lymphocytes are essential organizers of adaptive immune responses and key mediators in immune-mediated autoimmune and allergic diseases. Upon activation by the antigen-presenting cells (ARC), 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. TH1 cells make interferon g (IFNg) and regulate antigen presentation and cellular immunity. TH2 cells, on the other hand, secrete IL-4, -5 and -13, which together regulate humoral and anti-parasite immunity. The cytokine microenvironment during TH activation determines TH effector differentiation, through selective signal transducer and activator of transcription (STAT) proteins leading to expression of lineage-specific master transcription factors. Recently, a novel TH subset, named THIL-17, TH17 or THi, that make IL-17 has emerged as critical regulators of tissue inflammation. We found that TH17/THJ cells are a distinct lineage of TH cells from TH1 and TH2 cells and TH17/THi differentiation is negatively regulated by IFNg and IL-4. IL-6 and IL-23 synergize in TH17/TH1 differentiation through Stat3. This new grant aims at investigating the molecular programs governing TH17/THi differentiation. Our central hypothesis is that cytokine mediated STATS activation initiates TH17/THi-specific transcriptional and epigenetic programs. We will first investigate the function of STATS in TH17/THi differentiation and test if STATS functions to upregulate RORa and RORc during TH17/THJ differentiation. Secondly, we will investigate the function of RORa in TH17/THJ differentiation. Lastly, we will Investigate the molecular specification of TH17/THJ and inducible regulatory T (iTreg) cells. These studies will greatly benefit our understanding of the molecular programs governing TH17/THi differentiation and may suggest novel treatments of TH17/THi-mediated immune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR050772-10
Application #
8122304
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Mancini, Marie
Project Start
2003-09-26
Project End
2012-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
10
Fiscal Year
2011
Total Cost
$308,385
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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