Journal ArticleDOI
RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation
Laura Codarri,Gabor Gyülvészi,Vinko Tosevski,Lysann Hesske,Adriano Fontana,Laurent Magnenat,Tobias Suter,Burkhard Becher +7 more
TLDR
It is reported that interleukin 23 and the transcription factor RORγt drove expression of the cytokine GM-CSF in helper T cells, whereas IL-12, interferon-γ (IFN-γ) and IL-27 acted as negative regulators.Abstract:
Although the role of the T(H)1 and T(H)17 subsets of helper T cells as disease mediators in autoimmune neuroinflammation remains a subject of some debate, none of their signature cytokines are essential for disease development. Here we report that interleukin 23 (IL-23) and the transcription factor RORγt drove expression of the cytokine GM-CSF in helper T cells, whereas IL-12, interferon-γ (IFN-γ) and IL-27 acted as negative regulators. Autoreactive helper T cells specifically lacking GM-CSF failed to initiate neuroinflammation despite expression of IL-17A or IFN-γ, whereas GM-CSF secretion by Ifng(-/-)Il17a(-/-) helper T cells was sufficient to induce experimental autoimmune encephalomyelitis (EAE). During the disease effector phase, GM-CSF sustained neuroinflammation via myeloid cells that infiltrated the central nervous system. Thus, in contrast to all other known helper T cell-derived cytokines, GM-CSF serves a nonredundant function in the initiation of autoimmune inflammation regardless of helper T cell polarization.read more
Citations
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Protective and pathogenic functions of macrophage subsets
Peter J. Murray,Thomas A. Wynn +1 more
TL;DR: The four stages of orderly inflammation mediated by macrophages are discussed: recruitment to tissues; differentiation and activation in situ; conversion to suppressive cells; and restoration of tissue homeostasis.
Journal ArticleDOI
Immunopathology of multiple sclerosis
TL;DR: The current understanding of multiple sclerosis immunopathology is discussed, long-standing hypotheses regarding the role of the immune system in the disease are evaluated, and key questions that are still unanswered are delineated.
Journal ArticleDOI
The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing
TL;DR: This Review focuses on the recent advances that have been made regarding the transcriptional control of TH 17 cell plasticity and stability, as well as the effector functions of TH17 cells, and highlights the mechanisms of IL-17 signalling in mesenchymal and barrier epithelial tissues.
Journal ArticleDOI
Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells
Markus Kleinewietfeld,Arndt Manzel,Arndt Manzel,Jens Titze,Jens Titze,Heda Kvakan,Nir Yosef,Ralf A. Linker,Dominik N. Müller,Dominik N. Müller,David A. Hafler,David A. Hafler +11 more
TL;DR: It is shown that increased salt concentrations found locally under physiological conditions in vivo markedly boost the induction of murine and human TH17 cells, which display a highly pathogenic and stable phenotype characterized by the upregulation of the pro-inflammatory cytokines GM-CSF, TNF-α and IL-2.
Journal ArticleDOI
A Validated Regulatory Network for Th17 Cell Specification
Maria Ciofani,Aviv Madar,Aviv Madar,Carolina Galan,MacLean Sellars,Kieran Mace,Florencia Pauli,Ashish Agarwal,Wendy Huang,Christopher N. Parkurst,Michael Muratet,Kim M. Newberry,Sarah Meadows,Alex Greenfield,Yi Yang,Preti Jain,Francis K. Kirigin,Carmen Birchmeier,Erwin F. Wagner,Kenneth M. Murphy,Kenneth M. Murphy,Richard M. Myers,Richard Bonneau,Richard Bonneau,Dan R. Littman,Dan R. Littman +25 more
TL;DR: It is found that cooperatively bound BATF and IRF4 contribute to initial chromatin accessibility and, with STAT3, initiate a transcriptional program that is then globally tuned by the lineage-specifying TF RORγt, which plays a focal deterministic role at key loci.
References
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Journal ArticleDOI
Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.
Estelle Bettelli,Yijun Carrier,Wenda Gao,Thomas Korn,Terry B. Strom,Mohamed Oukka,Howard L. Weiner,Vijay K. Kuchroo +7 more
TL;DR: 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.
Journal ArticleDOI
The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.
Ivaylo I. Ivanov,Brent S. McKenzie,Liang Zhou,Carlos E. Tadokoro,Alice Lepelley,Juan J. Lafaille,Daniel J. Cua,Dan R. Littman +7 more
TL;DR: It is shown that the orphan nuclear receptor RORgammat is the key transcription factor that orchestrates the differentiation of this effector cell lineage of proinflammatory T helper cells and its potential as a therapeutic target in inflammatory diseases is highlighted.
Journal ArticleDOI
Interleukin 17–producing CD4 + effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages
Laurie E. Harrington,Robin D. Hatton,Paul R. Mangan,Henrietta Turner,Theresa L. Murphy,Kenneth M. Murphy,Casey T. Weaver +6 more
TL;DR: Findings provide a basis for understanding how inhibition of IFN-γ signaling enhances development of pathogenic TH-17 effector cells that can exacerbate autoimmunity.
Journal ArticleDOI
A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17
Heon Park,Zhaoxia Li,Xuexian O. Yang,Seon Hee Chang,Roza Nurieva,Yi Hong Wang,Ying Wang,Leroy Hood,Zhou Zhu,Qiang Tian,Chen Dong +10 more
TL;DR: 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.
Journal ArticleDOI
IL-23 drives a pathogenic T cell population that induces autoimmune inflammation
Claire L. Langrish,Yi Yi Chen,Wendy M. Blumenschein,Jeanine D. Mattson,Beth Basham,Jonathan D. Sedgwick,Terrill K. McClanahan,Robert A. Kastelein,Daniel J. Cua +8 more
TL;DR: 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.