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

• Published in: Nature immunology Vol. 12; no. 6; pp. 560 - 567
• Main Authors: Codarri, Laura, Gyülvészi, Gabor, Tosevski, Vinko, Hesske, Lysann, Fontana, Adriano, Magnenat, Laurent, Suter, Tobias, Becher, Burkhard
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2011; Nature Publishing Group
• Subjects: 631/250/127; 631/250/1619/554/1898; 631/250/249/1313; 631/45/612/822; Animals; Autoimmunity; Biomedical and Life Sciences; Biomedicine; Cells, Cultured; Encephalomyelitis, Autoimmune, Experimental - chemically induced; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Female; Flow Cytometry; Glycoproteins; Granulocyte-macrophage colony stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Granulocyte-Macrophage Colony-Stimulating Factor - immunology; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Immunology; Infectious Diseases; 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; Physiological aspects; T cells; 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; Switzerland
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/ni.2027

The development of experimental autoimmune encephalomyelitis has been attributed to cells of the T H 1 or T H 17 subset of helper T cells. Becher and Rostami and their colleagues show that IL-23-induced production of the cytokine GM-CSF underlies disease development and severity. 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.