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

doi:10.1016/j.cell.2006.07.035

The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells

Cell. 2006 Sep 22;126(6):1121-33. doi: 10.1016/j.cell.2006.07.035.

Authors

Ivaylo I Ivanov¹, Brent S McKenzie, Liang Zhou, Carlos E Tadokoro, Alice Lepelley, Juan J Lafaille, Daniel J Cua, Dan R Littman

Affiliation

¹ Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.

PMID: 16990136
DOI: 10.1016/j.cell.2006.07.035

Abstract

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 naïve CD4(+) T helper cells and is required for their expression in response to IL-6 and TGF-beta, the cytokines known to induce IL-17. Th17 cells are constitutively present throughout the intestinal lamina propria, express RORgammat, and are absent in mice deficient for RORgammat or IL-6. Mice with RORgammat-deficient T cells have attenuated autoimmune disease and lack tissue-infiltrating Th17 cells. Together, these studies suggest that RORgammat is a key regulator of immune homeostasis and highlight its potential as a therapeutic target in inflammatory diseases.

Publication types

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

MeSH terms

Animals
Autoimmune Diseases / genetics
Autoimmune Diseases / immunology
CD4 Antigens / genetics
CD4 Antigens / immunology
Cell Differentiation / genetics
Cell Differentiation / immunology*
Disease Models, Animal
Hematopoietic Stem Cells / immunology*
Hematopoietic Stem Cells / metabolism
Homeostasis / genetics
Homeostasis / immunology
Interleukin-17 / immunology*
Interleukin-17 / metabolism
Interleukin-6 / immunology
Interleukin-6 / metabolism
Intestinal Mucosa / cytology
Intestinal Mucosa / immunology*
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Nuclear Receptor Subfamily 1, Group F, Member 3
Protein Isoforms / genetics
Protein Isoforms / metabolism
Receptors, Retinoic Acid / genetics
Receptors, Retinoic Acid / metabolism*
Receptors, Thyroid Hormone / genetics
Receptors, Thyroid Hormone / metabolism*
T-Lymphocytes, Helper-Inducer / immunology*
T-Lymphocytes, Helper-Inducer / metabolism

Substances

CD4 Antigens
Interleukin-17
Interleukin-6
Nuclear Receptor Subfamily 1, Group F, Member 3
Protein Isoforms
Receptors, Retinoic Acid
Receptors, Thyroid Hormone
Rorc protein, mouse