Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocytes.
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 gamma-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-alpha, lymphotoxin-beta, 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/MIP3alpha, 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.
Pène
Jérôme
J
Institut National de la Santé et de la Recherche Médicale, Unité 844, Montpellier, France.
Chevalier
Sylvie
S
Preisser
Laurence
L
Vénéreau
Emilie
E
Guilleux
Marie-Hélène
MH
Ghannam
Soufiane
S
Molès
Jean-Pierre
JP
Danger
Yannic
Y
Ravon
Elisa
E
Lesaux
Sabine
S
Yssel
Hans
H
Gascan
Hugues
H
D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation; D016207:Cytokines / Q000032:analysis* / Q000276:immunology; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology; D008213:Lymphocyte Activation; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D054399:Receptors, CCR6 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000502:physiology; D018417:Th1 Cells / Q000502:physiology
C106311:CCR6 protein, human; D016207:Cytokines; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D054399:Receptors, CCR6; D019707:Receptors, Chemokine; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone