Interleukin 17 (IL-17)–producing T helper cells (TH-17 cells) have been characterized in mice as a distinct subset of effector cells, but their identity and properties in humans remain elusive. We report here that expression of CCR6 and CCR4 together identified human memory CD4+ T cells selectively producing IL-17 and expressing mRNA encoding the human ortholog of mouse RORγt, a transcription factor, whereas CCR6 and CXCR3 identified TH1 cells producing interferon-γ and T helper cells producing both interferon-γ and IL-17. Memory T cells specific for Candida albicans were present mainly in the CCR6+CCR4+ TH-17 subset, whereas memory T cells specific for Mycobacterium tuberculosis were present in CCR6+CXCR3+ T helper type 1 subset. The elicitation of IL-17 responses correlated with the capacity of C. albicans hyphae to stimulate antigen-presenting cells for the priming of TH-17 responses in vitro and for the production of IL-23 but not IL-12. Our results demonstrate that human TH-17 cells have distinct migratory capacity and antigenic specificities and establish a link between microbial products, T helper cell differentiation and homing in response to fungal antigens.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Cellular & Molecular Immunology Open Access 23 May 2023
Current Clinical Microbiology Reports Open Access 31 March 2023
Leukemia Open Access 31 January 2023
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Murphy, K.M. & Reiner, S.L. The lineage decisions of helper T cells. Nat. Rev. Immunol. 2, 933–944 (2002).
Veldhoen, M., Hocking, R.J., Atkins, C.J., Locksley, R.M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).
Mangan, P.R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).
Ivanov, I.I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).
Cua, D.J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003).
Oppmann, B. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13, 715–725 (2000).
Napolitani, G., Rinaldi, A., Bertoni, F., Sallusto, F. & Lanzavecchia, A. Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1–polarizing program in dendritic cells. Nat. Immunol. 6, 769–776 (2005).
Harrington, L.E. et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).
Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).
Kolls, J.K. & Linden, A. Interleukin-17 family members and inflammation. Immunity 21, 467–476 (2004).
Weaver, C.T., Hatton, R.D., Mangan, P.R. & Harrington, L.E. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol. 25, 821–852 (2007).
Ye, P. et al. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J. Exp. Med. 194, 519–527 (2001).
Happel, K.I. et al. Cutting edge: roles of Toll-like receptor 4 and IL-23 in IL-17 expression in response to Klebsiella pneumoniae infection. J. Immunol. 170, 4432–4436 (2003).
Murphy, C.A. et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J. Exp. Med. 198, 1951–1957 (2003).
Sallusto, F., Mackay, C.R. & Lanzavecchia, A. The role of chemokine receptors in primary, effector, and memory immune responses. Annu. Rev. Immunol. 18, 593–620 (2000).
Sallusto, F., Geginat, J. & Lanzavecchia, A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol. 22, 745–763 (2004).
Liao, F. et al. CC-chemokine receptor 6 is expressed on diverse memory subsets of T cells and determines responsiveness to macrophage inflammatory protein 3 α. J. Immunol. 162, 186–194 (1999).
Butcher, E.C. & Picker, L.J. Lymphocyte homing and homeostasis. Science 272, 60–66 (1996).
Bonecchi, R. et al. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J. Exp. Med. 187, 129–134 (1998).
Sallusto, F., Lenig, D., Mackay, C.R. & Lanzavecchia, A. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J. Exp. Med. 187, 875–883 (1998).
Liang, S.C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271–2279 (2006).
Rivino, L. et al. Chemokine receptor expression identifies Pre-T helper (Th)1, Pre-Th2, and nonpolarized cells among human CD4+ central memory T cells. J. Exp. Med. 200, 725–735 (2004).
Romani, L. Immunity to fungal infections. Nat. Rev. Immunol. 4, 1–23 (2004).
Veldhoen, M., Hocking, R.J., Flavell, R.A. & Stockinger, B. Signals mediated by transforming growth factor-β initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat. Immunol. 7, 1151–1156 (2006).
Messi, M. et al. Memory and flexibility of cytokine gene expression as separable properties of human TH1 and TH2 lymphocytes. Nat. Immunol. 4, 78–86 (2003).
Campbell, J.J. et al. The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells. Nature 400, 776–780 (1999).
Romagnani, S. Cytokines and chemoattractants in allergic inflammation. Mol. Immunol. 38, 881–885 (2002).
Wakugawa, M. et al. CC chemokine receptor 4 expression on peripheral blood CD4+ T cells reflects disease activity of atopic dermatitis. J. Invest. Dermatol. 117, 188–196 (2001).
Kohler, R.E., Caon, A.C., Willenborg, D.O., Clark-Lewis, I. & McColl, S.R. A role for macrophage inflammatory protein-3α/CC chemokine ligand 20 in immune priming during T cell-mediated inflammation of the central nervous system. J. Immunol. 170, 6298–6306 (2003).
Ruth, J.H. et al. Role of macrophage inflammatory protein-3α and its ligand CCR6 in rheumatoid arthritis. Lab. Invest. 83, 579–588 (2003).
Lukacs, N.W., Prosser, D.M., Wiekowski, M., Lira, S.A. & Cook, D.N. Requirement for the chemokine receptor CCR6 in allergic pulmonary inflammation. J. Exp. Med. 194, 551–555 (2001).
Homey, B. et al. Up-regulation of macrophage inflammatory protein-3α/CCL20 and CC chemokine receptor 6 in psoriasis. J. Immunol. 164, 6621–6632 (2000).
Schaerli, P. et al. Characterization of human T cells that regulate neutrophilic skin inflammation. J. Immunol. 173, 2151–2158 (2004).
Kikly, K., Liu, L., Na, S. & Sedgwick, J.D. The IL-23/Th(17) axis: therapeutic targets for autoimmune inflammation. Curr. Opin. Immunol. 18, 670–675 (2006).
Nakae, S., Nambu, A., Sudo, K. & Iwakura, Y. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J. Immunol. 171, 6173–6177 (2003).
Nakae, S. et al. IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc. Natl. Acad. Sci. USA 100, 5986–5990 (2003).
Cook, D.N. et al. CCR6 mediates dendritic cell localization, lymphocyte homeostasis, and immune responses in mucosal tissue. Immunity 12, 495–503 (2000).
Kwon, J.H., Keates, S., Bassani, L., Mayer, L.F. & Keates, A.C. Colonic epithelial cells are a major site of macrophage inflammatory protein 3α (MIP-3α) production in normal colon and inflammatory bowel disease. Gut 51, 818–826 (2002).
Keller, M. et al. T cell-regulated neutrophilic inflammation in autoinflammatory diseases. J. Immunol. 175, 7678–7686 (2005).
Kao, C.Y. et al. Up-regulation of CC chemokine ligand 20 expression in human airway epithelium by IL-17 through a JAK-independent but MEK/NF-κB-dependent signaling pathway. J. Immunol. 175, 6676–6685 (2005).
Kao, C.Y. et al. IL-17 markedly up-regulates beta-defensin-2 expression in human airway epithelium via JAK and NF-κB signaling pathways. J. Immunol. 173, 3482–3491 (2004).
Yang, D. et al. Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286, 525–528 (1999).
Khader, S.A. et al. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat. Immunol. 8, 369–377 (2007).
Del Prete, G.F. et al. Purified protein derivative of Mycobacterium tuberculosis and excretory-secretory antigen(s) of Toxocara canis expand in vitro human T cells with stable and opposite (type 1 T helper or type 2 T helper) profile of cytokine production. J. Clin. Invest. 88, 346–350 (1991).
Cruz, A. et al. Cutting edge: IFN-γ regulates the induction and expansion of IL-17-producing CD4 T cells during mycobacterial infection. J. Immunol. 177, 1416–1420 (2006).
Flynn, J.L. & Chan, J. Immunology of tuberculosis. Annu. Rev. Immunol. 19, 93–129 (2001).
Hohl, T.M., Rivera, A. & Pamer, E.G. Immunity to fungi. Curr. Opin. Immunol. 18, 465–472 (2006).
Khader, S.A. et al. IL-23 compensates for the absence of IL-12p70 and is essential for the IL-17 response during tuberculosis but is dispensable for protection and antigen-specific IFN-γ responses if IL-12p70 is available. J. Immunol. 175, 788–795 (2005).
Huang, W., Na, L., Fidel, P.L. & Schwarzenberger, P. Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J. Infect. Dis. 190, 624–631 (2004).
Urban, C.F., Reichard, U., Brinkmann, V. & Zychlinsky, A. Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cell. Microbiol. 8, 668–676 (2006).
Geginat, J., Sallusto, F. & Lanzavecchia, A. Cytokine-driven proliferation and differentiation of human naive, central memory, and effector memory CD4+ T cells. J. Exp. Med. 194, 1711–1719 (2001).
Sallusto, F. & Lanzavecchia, A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J. Exp. Med. 179, 1109–1118 (1994).
We thank M. Messi for help with initial experiments, and M. Manz and M. Uguccioni for critical reading and comments. Anti-α4β7 (Act1) was from C.R. Mackay (The Garvan institute). Supported by the Swiss National Science Foundation (31-101962 to F.S. and 31-112678 to A.L.), the European Commission FP6 Programme (LSHP-CT-2003-503240 (Mucosal Vaccines for Poverty-Related Diseases); LSB-CT-2005-518167 (Innovative Chemokine-Based Therapeutic Strategies for Autoimmunity and Chronic Inflammation)), the National Institutes of Health (U19 AI057266-01) and the Helmut Horten Foundation (for The Institute for Research in Biomedicine).
The authors declare no competing financial interests.
About this article
Cite this article
Acosta-Rodriguez, E., Rivino, L., Geginat, J. et al. Surface phenotype and antigenic specificity of human interleukin 17–producing T helper memory cells. Nat Immunol 8, 639–646 (2007). https://doi.org/10.1038/ni1467
This article is cited by
Nature Reviews Nephrology (2023)
Nature Immunology (2023)
Nature Reviews Gastroenterology & Hepatology (2023)
Cellular & Molecular Immunology (2023)