Chronically Inflamed Human Tissues Are Infiltrated by Highly Differentiated Th17 Lymphocytes

Abstract

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 γ-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-α, 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/MIP3α, 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.

In vivo activated monocytes from the site of inflammation in humans specifically promote Th17 responses

“…These data suggest that CD4 ϩ T cells migrating into inflamed joints could be driven by direct interactions with activated monocytes toward a Th17 phenotype, and, thus, participate in the inflammatory response. Although it has previously been shown that Th17 cells and IL-17 are present at sites of human autoimmune inflammation, including RA (22)(23)(24), MS (25), and psoriasis (24,26), to our knowledge, it has not been demonstrated that APC taken from a site of inflammation can promote Th17 responses. As such, our data provide an insight into the formation of these highly pathogenic cells in vivo, and suggest that targeting of inflammatory monocytes could lead not only to a decrease in the production of proinflammatory cytokines, but also in a reduction in Th17 cells.…”

Characterization of intratumoral follicular helper T cells in follicular lymphoma: role in the survival of malignant B cells

“…We also included in our analysis Th1, Th2 and Th17 clones derived from chronically inflamed human tissues that were shown to be highly representative of T-cell polarization in humans. 24,27 This study involved 45 genes that have a pivotal role in CD4 pos T cell differentiation, localization and effector functions (Supplementary Table S1). The results of a principal component analysis revealed that FL and tonsil-derived T FH shared a very close gene expression signature, compared with Th1, Th2, Th17, Treg and FL T FR (Figure 4a).…”

“…Th1, Th2 and Th17 clones were obtained from biopsies taken from active inflammatory lesions of patients suffering from chronic inflammatory or auto-immune diseases, as previously described. 24 Quantitative RT-PCR Total RNA was extracted using RNeasy Kit (Qiagen, Valencia, CA, USA). All samples used displayed an RNA integrity number of at least 9.4. cDNA was then generated using Superscript II reverse transcriptase (Invitrogen, Carlsbad, CA, USA).…”

IL-17A, But Not IL-17F, Is Indispensable for Airway Vascular Remodeling Induced by Exaggerated Th17 Cell Responses in Prolonged Ovalbumin-Challenged Mice

“…Research on allergic asthmatics has shown a significant increase in the percentage of Th17 cells in PBMCs and the plasma concentrations of IL-17 and IL-22, in proportion to the disease severity (7). This is supported by several studies in which increased IL-17A and IL-17F expression and Th17 cells in the tissues of asthmatics were observed (8)(9)(10). However, the role of Th17 cells in vascular remodeling in asthma remains to be elucidated.…”