Browsing by Author "Stritesky, Gretta L."

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    THE DEVELOPMENT AND COMMITMENT OF T HELPER SUBSETS
    (2011-03-09) Stritesky, Gretta L.; Kaplan, Mark H.; Blum, Janice Sherry, 1957-; Dent, Alexander L.; Harrington, Maureen A.
    T helper cells play a crucial role in providing protection against a wide variety of pathogens. The differentiation and effector function of T helper cell subsets is dependent on cytokine activation of Signal Transducer and Activator of Transcription (STAT) family members. The development of Th17 cells, which are important for immunity to fungi and extracellular bacteria, relies on STAT3. We show that IL-23 in combination with IL-1β promotes maintenance of the Th17 phenotype following multiple rounds of stimulation. However, IL-23 does not promote commitment of Th17 cells, and when Th17 cells are cultured with IL-12 or IL-4 they switch to a Th1 and Th2 phenotype, respectively. The maintenance of the Th17 phenotype by IL-23 also requires STAT4. STAT4-deficient memory cells cultured with IL-23 have reduced IL-17 production following stimulation with either anti-CD3 or IL-18+IL-23 stimulation compared to wild type memory cells. Furthermore, STAT4-deficient mice have impaired in vivo Th17 development following immunization with ovalbumin. This challenges a one-STAT/one-subset paradigm and suggests that multiple STAT proteins can contribute to a single phenotype. To test this further we examined whether STAT3 is required for the development of Th2 cells, a subset known to depend upon the IL-4-induced activation of STAT6 for immunity to parasites and promoting allergic inflammation. We demonstrate that in the absence of STAT3, the expression of Th2-associated cytokines and transcription factors is dramatically reduced. STAT3 is also required for in vivo development of Th2 cells. Moreover, allergic inflammation is diminished in mice that have T cells lacking expression of STAT3. STAT3 does not affect STAT6 activation, but does impact how STAT6 functions in binding target genes. Thus, multiple STAT proteins can cooperate in promoting the development of specific T helper subsets.
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    Th17 cells demonstrate stable cytokine production in a proallergic environment
    (The American Association of Immunologists, 2014-09-15) Glosson-Byers, Nicole L.; Sehra, Sarita; Stritesky, Gretta L.; Yu, Qing; Awe, Olufolakemi; Pham, Duy; Bruns, Heather A.; Kaplan, Mark H.; Department of Pediatrics, IU School of Medicine
    Th17 cells are critical for the clearance of extracellular bacteria and fungi, but also contribute to the pathology of autoimmune diseases and allergic inflammation. After exposure to an appropriate cytokine environment, Th17 cells can acquire a Th1-like phenotype, but less is known about their ability to adopt Th2 and Th9 effector programs. To explore this in more detail, we used an IL-17F lineage tracer mouse strain that allows tracking of cells that formerly expressed IL-17F. In vitro-derived Th17 cells adopted signature cytokine and transcription factor expression when cultured under Th1-, Th2-, or Th9-polarizing conditions. In contrast, using two models of allergic airway disease, Th17 cells from the lungs of diseased mice did not adopt Th1, Th2, or Th9 effector programs, but remained stable IL-17 secretors. Although in vitro-derived Th17 cells expressed IL-4Rα, those induced in vivo during allergic airway disease did not, possibly rendering them unresponsive to IL-4-induced signals. However, in vitro-derived, Ag-specific Th17 cells transferred in vivo to OVA and aluminum hydroxide-sensitized mice also maintained IL-17 secretion and did not produce alternative cytokines upon subsequent OVA challenge. Thus, although Th17 cells can adopt new phenotypes in response to some inflammatory environments, our data suggest that in allergic inflammation, Th17 cells are comparatively stable and retain the potential to produce IL-17. This might reflect a cytokine environment that promotes Th17 stability, and allow a broader immune response at tissue barriers that are susceptible to allergic inflammation.