Transcription factor requirements for the generation of IL-17-secreting T-cells | Posted on:2007-08-27 | Degree:Ph.D | Type:Dissertation | University:Indiana University | Candidate:Mathur, Anubhav Narain | Full Text:PDF | GTID:1444390005464219 | Subject:Health Sciences | Abstract/Summary: | | CD4+ T-cells coordinate immune responses to pathogens and auto-antigens. CD4+ T-cells activated in the presence of IL-12 develop into T-helper-1 (Th1) cells, a component of cell mediated immunity and autoimmune diseases, and is distinguished from other T-helper subsets by interferon-gamma (IFN-gamma) secretion. Stat4 (Signal Transducer and Activator of Transcription-4) and T-bet (T-box Expressed in T-cells) are required for the generation of Th1 cells and mice deficient in these factors fail to secrete wild type levels of IFN-gamma and are protected from inflammatory diseases. More recently, another subset of Th cells has been identified that secretes the hallmark cytokine IL-17.{09}IL-17secreting Th cells are critically involved in various immune responses and inflammatory diseases. Development of these cells is promoted in vivo and in vitro by IL-23 or TGFbeta1+IL-6. Despite growing interest in this novel inflammatory T-helper subset, little is known about the transcription factors that regulate their development. To define transcription factor requirements, we examined the generation of IL-17-secreting Th cells in T-cells deficient in Stat3, Stat4, and T-bet. Our results indicate that T-bet negatively regulates IL-23 mediated IL-17 secretion. IL-23 stimulated cells express Th1-specific transcription factors and cytokine receptors. Antigen-receptor mediated induction of T-bet in IL-23 differentiated cultures promotes its progression from an IL-17 to an IFN-gamma-secreting phenotype, suggesting that IL-23 induced IL-17-secretion is unstable. The overlapping Th phenotypes stimulated by IL-12 and IL-23 suggest that IL-23 differentiated cells are a component of type I immunity, and we have thus termed this phenotype: Th1beta. In contrast, IL-17 secreting cells generated by TGFbeta1+IL-6 are stable following multiple rounds of stimulation. We further demonstrate that Stat3 is not required for Th1 development buts required for the acquisition of IL-17-secreting phenotypes generated by either IL-23 or TGFbeta1+IL-6. In contrast, Stat4 is required for IL-23, but not TGFbeta1+IL-6 mediated development of IL-17-secreting Th cells. The differences in transcription factor requirements and the stability of Th1beta and TGFbeta1+IL-6 stimulated phenotypes, suggests these subsets may be distinct IL-17 secreting Th lineages. | Keywords/Search Tags: | Cells, IL-17, Transcription factor requirements, IL-23, Il-17-secreting, Tgfbeta1, Il-6, Generation | | Related items |
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