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The Protein Tyrosine Phosphatase SHP-1 Dampens Th17 Development

Mauldin, Ileana S.
Thesis/Dissertation; Online
Mauldin, Ileana S.
Tung, Kenneth
Ravichandran, Kodi
Lorenz, Ulrike M. Lorenz
Bender, Timothy
Hahn, Young
T helper 17 cells (Th17) represent a subset of CD4 + T helper cells that secrete the pro-inflammatory cytokines IL-17A and IL-17F. Th17 cells have been ascribed both a beneficial role in promoting clearance of pathogenic fungi and bacteria, and a pathogenic role in autoimmune diseases. Activation of the transcription factor STAT3 downstream of IL-6 or IL-21-mediated signaling has been shown to be essential for Th17 differentiation; however how STAT3 is regulated is still poorly understood. Previous work done on cancer cell lines demonstrated that the protein tyrosine phosphatase SHP-1 may be a negative regulator of JAK/STAT signaling. Based on this work we hypothesized that SHP-1 may negatively regulate JAK/STAT3 signaling, and therefore influence Th17 development. In studies displayed in chapter three, we identify that SHP-1 is a critical regulator of Th17 development, using three complementary approaches. Impaired SHP-1 activity through genetic deletion of SHP-1, transgenic expression of an inducible dominant negative SHP-1, or pharmacological inhibition of SHP-1 strongly promotes the development of Th17. Ex vivo Th17 skewing assays demonstrate that genetic or pharmacological disruption of SHP-1 activity in T cells results in a hyper-response to stimulation via IL-6 and IL-21, two cytokines that promote Th17 development. Mechanistically, we identify that SHP-1 decreases the overall cytokine-induced phosphorylation of STAT3 in primary CD4 + T cells. These data identify SHP-1 as a key modifier of IL-6 and IL-21-driven Th17 development via regulation of STAT3 signaling, and suggest SHP-1 as a potential new therapeutic target for manipulating Th17 differentiation in vivo. iii During my studies investigating whether SHP-1 is a negative regulator of JAK/STAT3 signaling and Th17 development, we addressed several additional related questions in SHP-1-deficient mice, these studies are discussed in chapter four. Note: Abstract extracted from PDF text
University of Virginia, Department of Microbiology, Immunology, and Cancer Biology, PHD (Doctor of Philosophy), 2012
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PHD (Doctor of Philosophy)
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