Lecture 16- Autoimmunity II & Allergy

Lecture 16- Autoimmunity II & Allergy - The Orphan...

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The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Pro-inflammatory IL-17 + T Helper Cells Ivanov et al, 2006, Cell What the authors knew when they began this study: Th17 cells had been recently described as a separate T cell lineage in addition to Th1 and Th2 cells Many autoimmune diseases previously thought to be Th1-mediated are believed to be Th17 (IL-17) dependent: T-bet knockouts develop disease and IL-17 neutralization prevents disease The nuclear orphan receptor, ROT g t, is expressed on LTi cells of ILFs and on double positive thymocytes. But their expression in peripheral T cells was unknown Question: what is the phenotype of ROR g t+ T cells and how does ROR t affect T cell development and function?
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Figure 1 A. Using ROR g t-GFP reporter mice, ROR g t appears to be expressed (at low levels) in both TCR ab and TCR gd T cells of the gut. The majority of GFP staining is in lineage negative cells (Lin-), implying they are non-hematopoietic cells, probably LTi cells. B. ROR g t knockout animals display reduced TCR ab cells that are transcribing ROR g t, and completely lack TCR gd T cells and LTi cells that express ROR g t
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Figure 2 A. Previous work had shown that ROR g t expression is elevated in in vitro polarize Th17 cells. This suggests a link between ROR g t and IL-17. Indeed, only ROR g t+ cells express IL-17. B. Among ROR g t+ cells, approximately 10% of the CD4+ T cells express IL-17. Very importantly, in ROR g t- cells, this is significantly reduced. IFN g levels were not affected considerably. ROR g t+ and IL-17+ cells are highly enriched in the gut, but not in systemic tissues
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Figure 3 A. Under Th17 polarizing conditions, naïve T cells from wild-type mice produced IL-17 whereas ROR g t- T cells did not. No change in IFN g was observed B. TCR ligation in the presence of IL-6 and TGF b induced the rapid expression of ROR g t, and a delayed expression of IL-17A and IL-17F C. IL-6 or TGF b alone was able to induce minimal ROR g t, but no IL-17
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