The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells

@article{Ivanov2006TheON,
  title={The Orphan Nuclear Receptor ROR$\gamma$t Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells},
  author={I. Ivanov and B. McKenzie and Liang-Ji Zhou and C. Tadokoro and A. Lepelley and J. Lafaille and D. Cua and D. Littman},
  journal={Cell},
  year={2006},
  volume={126},
  pages={1121-1133}
}
IL-17-producing T lymphocytes have been recently shown to comprise a distinct lineage of proinflammatory T helper cells, termed Th17 cells, that are major contributors to autoimmune disease. We show here that the orphan nuclear receptor RORgammat is the key transcription factor that orchestrates the differentiation of this effector cell lineage. RORgammat induces transcription of the genes encoding IL-17 and the related cytokine IL-17F in naive CD4(+) T helper cells and is required for their… Expand

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References

SHOWING 1-10 OF 63 REFERENCES
IL-23 drives a pathogenic T cell population that induces autoimmune inflammation
TLDR
Using passive transfer studies, it is confirmed that these IL-23–dependent CD4+ T cells are highly pathogenic and essential for the establishment of organ-specific inflammation associated with central nervous system autoimmunity. Expand
A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17
TLDR
In vivo, antibody to IL- 17 inhibited chemokine expression in the brain during experimental autoimmune encephalomyelitis, whereas overexpression of IL-17 in lung epithelium caused Chemokine production and leukocyte infiltration, indicating a unique T helper lineage that regulates tissue inflammation. Expand
Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages
TLDR
Findings provide a basis for understanding how inhibition of IFN-γ signaling enhances development of pathogenic TH-17 effector cells that can exacerbate autoimmunity. Expand
TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.
TLDR
The data indicate that, in the presence of IL-6, TGFbeta1 subverts Th1 and Th2 differentiation for the generation ofIL-17-producing T cells. Expand
Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells
TLDR
It is shown that IL-6, an acute phase protein induced during inflammation, completely inhibits the generation of Foxp3+ Treg cells induced by TGF-β, and the data demonstrate a dichotomy in thegeneration of pathogenic (TH17) T cells that induce autoimmunity and regulatory (Foxp3+) T Cells that inhibit autoimmune tissue injury. Expand
Interleukin-23 Promotes a Distinct CD4 T Cell Activation State Characterized by the Production of Interleukin-17*
TLDR
Evidence is presented that murine IL-23, which is produced by activated dendritic cells, acts on memory T cells, resulting in elevated IL-17 secretion, which suggests that during a secondary immune response, IL- 23 can promote an activation state with features distinct from the well characterized Th1 and Th2 profiles. Expand
Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells
  • C. Dong
  • Medicine, Biology
  • Nature Reviews Immunology
  • 2006
TLDR
It is proposed that IL-17-producing CD4+ T cells represent a distinct inflammatory TH-cell lineage and have crucial roles in regulating tissue inflammation and the development of disease in several animal models of autoimmunity. Expand
The Transcription Factor GATA-3 Is Necessary and Sufficient for Th2 Cytokine Gene Expression in CD4 T Cells
TLDR
In transgenic mice, elevated GATA-3 in CD4 T cells caused Th2 cytokine gene expression in developing Th1 cells, indicating that Gata-3 is necessary and sufficient for Th2inflammatory gene expression. Expand
Understanding the IL-23-IL-17 immune pathway.
TLDR
By comparing the pathophysiological function of IL-12 and IL-23 in the context of host defense and autoimmune inflammation, the authors are beginning to understand the novelIL-23-IL-17 immune pathway. Expand
Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis.
TLDR
Treatment with anti-IL-23p19 effectively inhibited multiple inflammatory pathways that are critical for driving CNS autoimmune inflammation and prevented subsequent disease relapse. Expand
...
1
2
3
4
5
...