Identification of IL-17-producing FOXP3⁺ regulatory T cells in humans

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 12; pp. 4793 - 4798
• Main Authors: Voo, Kui Shin, Wang, Yui-Hsi, Santori, Fabio R, Boggiano, Cesar, Wang, Yi-Hong, Arima, Kazuhiko, Bover, Laura, Hanabuchi, Shino, Khalili, Jahan, Marinova, Ekaterina, Zheng, Biao, Littman, Dan R, Liu, Yong-Jun
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 24.03.2009; National Acad Sciences
• Subjects: Biological Sciences; Cells; Cellular differentiation; Cellular immunity; Clone Cells; Cloning; Cytokines; Forkhead Transcription Factors - immunology; Gene expression; Humans; Inflammation; Interleukin-17 - biosynthesis; Interleukin-2 - pharmacology; Interleukin-2 Receptor alpha Subunit - immunology; Interleukin-23 - pharmacology; Interleukin-6 - pharmacology; Interleukins; Interleukins - pharmacology; Memory; Neutrophils; Nuclear Receptor Subfamily 1, Group F, Member 3; Palatine Tonsil - cytology; Palatine Tonsil - drug effects; Palatine Tonsil - immunology; Palatine tonsils; Receptors, Retinoic Acid - immunology; Receptors, Thyroid Hormone - immunology; Signal transduction; Studies; T cell receptors; T lymphocytes; T-Lymphocyte Subsets - cytology; T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Transponders
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0900408106

IL-17-producing CD4⁺ T helper (Th17) cells have recently been defined as a unique subset of proinflammatory helper cells whose development depends on signaling initiated by IL-6 and TGF-β, autocrine activity of IL-21, activation of STAT3, and induction of the orphan nuclear receptor RORγt. The maintenance, expansion, and further differentiation of the committed Th17 cells depend on IL-1β and IL-23. IL-17 was originally found produced by circulating human CD45RO⁺ memory T cells. A recent study found that human Th17 memory cells selectively express high levels of CCR6. In this study, we report that human peripheral blood and lymphoid tissue contain a significant number of CD4⁺FOXP3⁺ T cells that express CCR6 and have the capacity to produce IL-17 upon activation. These cells coexpress FOXP3 and RORγt transcription factors. The CD4⁺FOXP3⁺CCR6⁺ IL-17-producing cells strongly inhibit the proliferation of CD4⁺ responder T cells. CD4⁺CD25high-derived T-cell clones express FOXP3, RORγt, and IL-17 and maintain their suppressive function via a cell-cell contact mechanism. We further show that human CD4⁺FOXP3⁺CCR6⁻ regulatory T (Treg) cells differentiate into IL-17 producer cells upon T-cell receptor stimulation in the presence of IL-1β, IL-2, IL-21, IL-23, and human serum. This, together with the finding that human thymus does not contain IL-17-producing Treg cells, suggests that the IL-17⁺FOXP3⁺ Treg cells are generated in the periphery. IL-17-producing Treg cells may play critical roles in antimicrobial defense, while controlling autoimmunity and inflammation.