Optimal induction of T helper 17 cells in humans requires T cell receptor ligation in the context of Toll-like receptor-activated monocytes

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 43; pp. 17034 - 17039
• Main Authors: Evans, Hayley G, Suddason, Tesha, Jackson, Ian, Taams, Leonie S, Lord, Graham M
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23-10-2007; National Acad Sciences
• Subjects: Autoimmune diseases; Biological Sciences; Biological variation; Cell Communication - drug effects; Cell culture techniques; Cellular biology; Cultured cells; Cytokines; Delta cells; Forkhead Transcription Factors - metabolism; Gene expression; Humans; Inductive reasoning; Interleukin-17 - immunology; Interleukin-2 Receptor alpha Subunit - metabolism; Interleukin-6 - pharmacology; Lymphocyte Activation; Medical research; Memory; Monocytes; Monocytes - cytology; Monocytes - drug effects; Monocytes - immunology; Receptors, Antigen, T-Cell - immunology; Rodents; T cell receptors; T lymphocytes; T-Lymphocytes, Helper-Inducer - cytology; T-Lymphocytes, Helper-Inducer - drug effects; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Regulatory - drug effects; Th1 Cells - drug effects; Th1 Cells - immunology; Th2 Cells - drug effects; Th2 Cells - immunology; Toll-Like Receptors - immunology; Transforming Growth Factor beta - pharmacology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0708426104

Recently, a new lineage of CD4⁺ T cells has been described in the mouse that specifically secretes IL-17 [T helper (Th) 17]. This discovery has led to a revision of the hypothesis that many autoimmune diseases are predominantly a Th1 phenomenon and may instead be critically dependent on the presence of Th17 cells. Murine Th17 cells differentiate from naïve T cell precursors in the presence of TGF-β and IL-6 or IL-21. However, given their putative importance in human autoimmunity, very little is known about the pathways that control the expression of IL-17 in humans. Here we show that the factors that determine the expression of IL-17 in human CD4⁺ T cells are completely different from mice. IL-6 and IL-21 were unable to induce IL-17 expression in either naïve or effector T cells, and TGF-β actually inhibited IL-17 expression. The expression of IL-17 was maximally induced from precommitted precursors present in human peripheral blood by cell-cell contact with Toll-like receptor-activated monocytes in the context of T cell receptor ligation. Furthermore, unlike IFN-γ, IL-17 expression was not suppressed by the presence of FOXP3⁺ regulatory CD4⁺ T cells. Taken together, these data indicate that human and mouse Th17 cells have important biological differences that may be of critical importance in the development of therapeutic interventions in diseases characterized by aberrant T cell polarization.