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Chronically Inflamed Human Tissues Are Infiltrated by Highly Differentiated Th17 Lymphocytes

Jérôme Pène^*, Sylvie Chevalier, Laurence Preisser, Emilie Vénéreau, Marie-Hélène Guilleux, Soufiane Ghannam^*, Jean-Pierre Molès, Yannic Danger, Elisa Ravon, Sabine Lesaux, Hans Yssel^1,* and Hugues Gascan^1,

^* Institut National de la Santé et de la Recherche Médicale, Unité 844, Montpellier, France; Institut National de la Santé et de la Recherche Médicale, Unité mixte 564, Université d’Angers, Angers, France; and Institut Universitaire de Recherche Clinique, Montpellier, France

Chronic inflammatory diseases are characterized by local tissue injury caused by immunocompetent cells, in particular CD4⁺ T lymphocytes, that are involved in the pathogenesis of these disorders via the production of distinctive sets of cytokines. Here, we have characterized single CD4⁺ T cells that infiltrate inflamed tissue taken from patients with psoriasis, Crohn’s disease, rheumatoid arthritis, or allergic asthma. Results from a cytokine production and gene profile analysis identified a population of in vivo differentiatedretinoid-related orphan receptor -expressing T cells, producing high levels of IL-17, that can represent up to 30% of infiltrating T lymphocytes. Activated Th17 cells produced IL-26, TNF-, lymphotoxin-β, and IL-22. IL-17 and IL-22 concentrations secreted by tissue infiltrating Th17 cells could reach up to 100 nM and were inversely correlated with the production of Th1- and Th2-associated cytokines. In addition, tissue-infiltrating Th17 cells are also characterized by high cell surface expression of CCR6, a chemokine receptor that was not expressed by Th1 and Th2 cells, isolated from the same lesions, and by the production of CCL20/MIP3, a CCR6 ligand, associated with tissue infiltration. Culture supernatants of activated Th17 cells, isolated from psoriatic lesions, induced the expression of gene products associated with inflammation and abnormal keratinocyte differentiation in an IL-17 and IL-22-dependent manner. These results show that tissue-infiltrating Th17 cells contribute to human chronic inflammatory disease via the production of several inflammatory cytokines and the creation of an environment contributing to their migration and sequestration at sites of inflammation.

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¹ Address correspondence and reprint requests to Dr. Hugues Gascan, Institut National de la Santé et de la Recherche Médicale, Unité mixte 564, Université d’Angers, 49033 Angers Cedex, France. E-mail address: gascan{at}univ-angers.fr or Dr. Hans Yssel, Institut National de la Santé et de la Recherche Médicale, Unité 844, 80 Rue Augustin Fliche, Montpellier Cedex 34091, France. E-mail address: hans.yssel{at}inserm.fr

² Abbreviations used in this paper: RORC, retinoid-related orphan receptor ; LT, lymphotoxin; RORt, retinoid-related orphan receptor t.