The Protein Tyrosine Phosphatase SHP-1 Dampens Th17 Development

Mauldin, Ileana S., Department of Microbiology, Immunology, and Cancer Biology, University of Virginia
Lorenz, Ulrike M. Lorenz, Department of Microbiology, Immunology, and Cancer Biology, University of Virginia
Hahn, Young, Department of Microbiology, University of Virginia
Ravichandran, Kodi, Department of Microbiology, University of Virginia
Tung, Kenneth, Department of Pathology, University of Virginia
Bender, Timothy, Department of Microbiology, University of Virginia

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

PHD (Doctor of Philosophy)
All rights reserved (no additional license for public reuse)
Issued Date: