Browsing by Author "Verdan, Felipe Fortino"

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    STAT3 activation impairs the stability of Th9 cells
    (American Association of Immunologists, 2017-03-15) Ulrich, Benjamin J.; Verdan, Felipe Fortino; McKenzie, Andrew N.J.; Kaplan, Mark H.; Olson, Matthew R.; Microbiology and Immunology, School of Medicine
    Th9 cells regulate multiple immune responses including immunity to pathogens and tumors, allergic inflammation, and autoimmunity. Despite ongoing research into Th9 development and function, little is known about the stability of the Th9 phenotype. In this report we demonstrate that IL-9 production is progressively lost in Th9 cultures over several rounds of differentiation. The loss of IL-9 is not due to an outgrowth of cells that do not secrete IL-9, as purified IL-9 secretors demonstrate the same loss of IL-9 in subsequent rounds of differentiation. The loss of IL-9 production correlates with increases in phospho-STAT3 levels within the cell, and the production of IL-10. STAT3-deficient Th9 cells have increased IL-9 production that is maintained for longer in culture than IL-9 in control cultures. IL-10 is responsible for STAT3 activation during the first round of differentiation, and contributes to instability in subsequent rounds of culture. Together, our results indicate that environmental cues dictate the instability of the Th9 phenotype, and suggest approaches to enhance Th9 activity in beneficial immune responses.
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    STAT3 Impairs STAT5 Activation in the Development of IL-9-Secreting T Cells
    (The American Association of Immunologists, Inc., 2016-04-15) Olson, Matthew R.; Verdan, Felipe Fortino; Hufford, Matthew M.; Dent, Alexander L.; Kaplan, Mark H.; Pediatrics, School of Medicine
    Th cell subsets develop in response to multiple activating signals, including the cytokine environment. IL-9-secreting T cells develop in response to the combination of IL-4 and TGF-β, although they clearly require other cytokine signals, leading to the activation of transcription factors including STAT5. In Th17 cells, there is a molecular antagonism of STAT5 with STAT3 signaling, although whether this paradigm exists in other Th subsets is not clear. In this paper, we demonstrate that STAT3 attenuates the ability of STAT5 to promote the development of IL-9-secreting T cells. We demonstrate that production of IL-9 is increased in the absence of STAT3 and cytokines that result in a sustained activation of STAT3, including IL-6, have the greatest potency in repressing IL-9 production in a STAT3-dependent manner. Increased IL-9 production in the absence of STAT3 correlates with increased endogenous IL-2 production and STAT5 activation, and blocking IL-2 responses eliminates the difference in IL-9 production between wild-type and STAT3-deficient T cells. Moreover, transduction of developing Th9 cells with a constitutively active STAT5 eliminates the ability of IL-6 to reduce IL-9 production. Thus, STAT3 functions as a negative regulator of IL-9 production through attenuation of STAT5 activation and function.