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

doi:10.1038/ni.2027

RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation

Nat Immunol. 2011 Jun;12(6):560-7. doi: 10.1038/ni.2027. Epub 2011 Apr 24.

Authors

Laura Codarri¹, Gabor Gyülvészi, Vinko Tosevski, Lysann Hesske, Adriano Fontana, Laurent Magnenat, Tobias Suter, Burkhard Becher

Affiliation

¹ Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.

PMID: 21516112
DOI: 10.1038/ni.2027

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cells, Cultured
Encephalomyelitis, Autoimmune, Experimental / chemically induced
Encephalomyelitis, Autoimmune, Experimental / immunology
Encephalomyelitis, Autoimmune, Experimental / metabolism*
Female
Flow Cytometry
Glycoproteins
Granulocyte-Macrophage Colony-Stimulating Factor / genetics
Granulocyte-Macrophage Colony-Stimulating Factor / immunology
Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
Interferon-gamma / genetics
Interferon-gamma / immunology
Interferon-gamma / pharmacology
Interleukin-12 / pharmacology
Interleukin-17 / genetics
Interleukin-17 / immunology
Interleukin-23 / pharmacology
Interleukins / pharmacology
Male
Mice
Mice, Inbred C57BL
Mice, Inbred Strains
Mice, Knockout
Mice, Transgenic
Myelin-Oligodendrocyte Glycoprotein
Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology
Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism*
Peptide Fragments
T-Lymphocytes, Helper-Inducer / immunology
T-Lymphocytes, Helper-Inducer / metabolism*
Th1 Cells / drug effects
Th1 Cells / immunology
Th1 Cells / metabolism
Th17 Cells / drug effects
Th17 Cells / immunology
Th17 Cells / metabolism

Substances

Glycoproteins
Il27 protein, mouse
Interleukin-17
Interleukin-23
Interleukins
Myelin-Oligodendrocyte Glycoprotein
Nuclear Receptor Subfamily 1, Group F, Member 3
Peptide Fragments
myelin oligodendrocyte glycoprotein (35-55)
Interleukin-12
Interferon-gamma
Granulocyte-Macrophage Colony-Stimulating Factor