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Th17 cytokines: The good, the bad, and the unknown
Cytokine & Growth Factor Reviews 21 (2010) 403–404
Contents lists available at ScienceDirect
Cytokine & Growth Factor Reviews journal homepage: www.elsevier.com/locate/cytogfr
Editorial
Th17 cytokines: The good, the bad, and the unknown
The identification of a new T cell subset referred to as T helper 17 (Th17) cells that produce the cytokines IL-17, IL-17F, IL-21 and IL-22 has fundamentally changed the Th1/Th2 dichotomy paradigm. Th17 cytokines can have protective roles in pathogen clearance and in vaccine-induced immunity or can have pathological roles in autoimmune diseases and inflammation. In this special issue of Cytokine and Growth Factor Reviews, we summarize recent progress in our understanding of the factors that regulate Th17 effector function, sources of Th17 cytokines and the protective and pathological roles of Th17 cytokines in health and disease. Until recently, effector CD4+ T helper cells had been classified into T helper1 (Th1) and T helper2 (Th2) effectors, based on signature cytokines they produce. Th1 effector cells produced the cytokine Interferon-gamma (IFN-g) and are thought to regulate immunity against intracellular infections, whereas Th2 effector cells produced the cytokines interleukin (IL)-4, IL-5 and IL-13 and are thought to mediate humoral immunity against parasite infections and atopy [1]. The distinct requirement for IL-12 and T-bet in Th1 differentiation, and IL-4 and GATA-3 for Th2 differentiation, further delineated the basis for the Th1/Th2 dichotomy. Accordingly, the Th1/Th2 cell dichotomy formed the basis of our understanding of T cell biology in health and disease for over two decades. However, several conflicting discrepancies between observations seen in IL-12p40 deficient mice and IFNg deficient mice in models of infection and autoimmune diseases were noted. For example, mice deficient in the IL-12p40 gene were more susceptible to autoimmune diseases and opportunistic infections, while IFNg gene deficient mice were not [2–5]. Also, most of the early studies that targeted the Th1 pathway used IL12p40 depleting antibody, resulting in similar confounding observations. These studies suggested that other CD4 T helper lineage cells may exist and function to provide protection or pathology in these models. The seminal discovery that IL-12p40 could combine with a new subunit IL-23p19 to form the functional cytokine IL-23, provided a logical basis to address these discrepancies [6]. Furthermore, identification that polarizing cytokines could drive the expression of IL-17 in Th cells, directed attention to the characterization of a new Th subset [7]. Accordingly, functional characterization of T helper-17 (Th17) cells as a distinct lineage set the stage for a change in the Th1/Th2 dichotomy to include a new Th subset called Th17 cells [8,9]. In the years following this initial discovery, many laboratories substantiated the role of Th17 cells in a variety of models in health and disease, and it became clear that Th17 cells produce the cytokines IL-17, IL-17F, IL-22 and IL-21. It also became evident that like Th1 and Th2 cells, there were specific polarizing cytokines – TGFb, IL-6 and IL-23 – and specific transcription factors
1359-6101/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.cytogfr.2010.10.008
– RORa and RORg – required for Th17 differentiation and maintenance. We also understood that the requirements for human and murine Th17 cell differentiation were not identical [10]. Importantly, it became clear that Th17 lineage cells produce cytokines that mediate immune responses that are both good and bad. Accordingly, the mechanistic understanding of the pathological role of Th17 cytokines in autoimmune diseases [3,11] has allowed us to appreciate the protective role of Th17 cytokines in immunity to pathogens [12]. Furthermore, we now understand some of the fine regulatory mechanisms in place that limit the inflammatory Th17 responses [8], and how dysregulation causes disease. In addition to Th17 cells, the identification of different innate cellular sources that produce IL-17 and IL-22, have further implicated these cytokines at the crossroads of innate and adaptive immunity. We have begun to explore the cells and the molecular signaling networks involved in eliciting downstream effects of Th17 responses. We have also observed versatility and plasticity in the Th17 lineage, projecting the adaptability of the host T helper effector cells to ever changing demands of the host immune system. Several of the key findings made in the past decade in Th17 biology are summarized in this special issue of Cytokine and Growth Factor Reviews focusing on the Th17 cytokines. We have gathered some of the world leaders in cellular and molecular immunology to provide a current overview of Th17 biology in health and disease. These reviews not only summarize our current understanding of the generation, role and effector function of Th17 cells and Th17 cytokines, but also discuss new perspectives that will serve to propel the field forward. At the same time, these reviews also address what remains unknown in the Th17 field and future avenues of research. References [1] Mossman T, Coffman R. Th1 and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 1989;7: 145–73. [2] Becher B, Durell B, Noelle R. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J Clin Invest 2002;110:493–7. [3] Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature (London) 2003;421:744–8. [4] Farah CS, Hu Y, Riminton S, Ashman RB. Distinct roles for interleukin-12p40 and tumour necrosis factor in resistance to oral candidiasis defined by genetargeting. Oral Microbiol Immun 2006;21:252–5. [5] Garvy BA, Wiley JA, Gigliotti F, Harmsen AG. Protection against Pneumocystis carinii pneumonia by antibodies generated from either T helper 1 or T helper 2 responses. Infect Immun 1997;65:5052–6. [6] Oppmann B, Lesley R, Blom B, Timans J, Xu Y, Hunte 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 2000;13:715–25.
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Editorial / Cytokine & Growth Factor Reviews 21 (2010) 403–404
[7] Infante-Duarte C, Horton HF, Byrne MC, Kamradt T. Microbial lipopeptides induce the production of IL-17 in Th cells. J Immunol 2000;165:6107–15. [8] Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005;6:1133–41. [9] Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, 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 2005;6: 1123–32. [10] Annunziato F, Cosmi L, Romagnani S. Human and murine Th17. Curr Opin HIV AIDS 2010;5:114–9. [11] Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 2003;198:1951–7. [12] Khader SA, Gaffen SL, Kolls JK. Th17 cells at the crossroads of innate and adaptive immunity against infectious diseases at the mucosa. Mucosal Immunol 2009;2:403–11.
Shabaana A. Khader* Division of Infectious Diseases, Department of Pediatrics, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States *Tel.: +1 412 692 7767; fax: +1 412 692 7636 E-mail address: [email protected] Available online 12 November 2010
Contents lists available at ScienceDirect
Cytokine & Growth Factor Reviews journal homepage: www.elsevier.com/locate/cytogfr
Editorial
Th17 cytokines: The good, the bad, and the unknown
The identification of a new T cell subset referred to as T helper 17 (Th17) cells that produce the cytokines IL-17, IL-17F, IL-21 and IL-22 has fundamentally changed the Th1/Th2 dichotomy paradigm. Th17 cytokines can have protective roles in pathogen clearance and in vaccine-induced immunity or can have pathological roles in autoimmune diseases and inflammation. In this special issue of Cytokine and Growth Factor Reviews, we summarize recent progress in our understanding of the factors that regulate Th17 effector function, sources of Th17 cytokines and the protective and pathological roles of Th17 cytokines in health and disease. Until recently, effector CD4+ T helper cells had been classified into T helper1 (Th1) and T helper2 (Th2) effectors, based on signature cytokines they produce. Th1 effector cells produced the cytokine Interferon-gamma (IFN-g) and are thought to regulate immunity against intracellular infections, whereas Th2 effector cells produced the cytokines interleukin (IL)-4, IL-5 and IL-13 and are thought to mediate humoral immunity against parasite infections and atopy [1]. The distinct requirement for IL-12 and T-bet in Th1 differentiation, and IL-4 and GATA-3 for Th2 differentiation, further delineated the basis for the Th1/Th2 dichotomy. Accordingly, the Th1/Th2 cell dichotomy formed the basis of our understanding of T cell biology in health and disease for over two decades. However, several conflicting discrepancies between observations seen in IL-12p40 deficient mice and IFNg deficient mice in models of infection and autoimmune diseases were noted. For example, mice deficient in the IL-12p40 gene were more susceptible to autoimmune diseases and opportunistic infections, while IFNg gene deficient mice were not [2–5]. Also, most of the early studies that targeted the Th1 pathway used IL12p40 depleting antibody, resulting in similar confounding observations. These studies suggested that other CD4 T helper lineage cells may exist and function to provide protection or pathology in these models. The seminal discovery that IL-12p40 could combine with a new subunit IL-23p19 to form the functional cytokine IL-23, provided a logical basis to address these discrepancies [6]. Furthermore, identification that polarizing cytokines could drive the expression of IL-17 in Th cells, directed attention to the characterization of a new Th subset [7]. Accordingly, functional characterization of T helper-17 (Th17) cells as a distinct lineage set the stage for a change in the Th1/Th2 dichotomy to include a new Th subset called Th17 cells [8,9]. In the years following this initial discovery, many laboratories substantiated the role of Th17 cells in a variety of models in health and disease, and it became clear that Th17 cells produce the cytokines IL-17, IL-17F, IL-22 and IL-21. It also became evident that like Th1 and Th2 cells, there were specific polarizing cytokines – TGFb, IL-6 and IL-23 – and specific transcription factors
1359-6101/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.cytogfr.2010.10.008
– RORa and RORg – required for Th17 differentiation and maintenance. We also understood that the requirements for human and murine Th17 cell differentiation were not identical [10]. Importantly, it became clear that Th17 lineage cells produce cytokines that mediate immune responses that are both good and bad. Accordingly, the mechanistic understanding of the pathological role of Th17 cytokines in autoimmune diseases [3,11] has allowed us to appreciate the protective role of Th17 cytokines in immunity to pathogens [12]. Furthermore, we now understand some of the fine regulatory mechanisms in place that limit the inflammatory Th17 responses [8], and how dysregulation causes disease. In addition to Th17 cells, the identification of different innate cellular sources that produce IL-17 and IL-22, have further implicated these cytokines at the crossroads of innate and adaptive immunity. We have begun to explore the cells and the molecular signaling networks involved in eliciting downstream effects of Th17 responses. We have also observed versatility and plasticity in the Th17 lineage, projecting the adaptability of the host T helper effector cells to ever changing demands of the host immune system. Several of the key findings made in the past decade in Th17 biology are summarized in this special issue of Cytokine and Growth Factor Reviews focusing on the Th17 cytokines. We have gathered some of the world leaders in cellular and molecular immunology to provide a current overview of Th17 biology in health and disease. These reviews not only summarize our current understanding of the generation, role and effector function of Th17 cells and Th17 cytokines, but also discuss new perspectives that will serve to propel the field forward. At the same time, these reviews also address what remains unknown in the Th17 field and future avenues of research. References [1] Mossman T, Coffman R. Th1 and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 1989;7: 145–73. [2] Becher B, Durell B, Noelle R. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J Clin Invest 2002;110:493–7. [3] Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature (London) 2003;421:744–8. [4] Farah CS, Hu Y, Riminton S, Ashman RB. Distinct roles for interleukin-12p40 and tumour necrosis factor in resistance to oral candidiasis defined by genetargeting. Oral Microbiol Immun 2006;21:252–5. [5] Garvy BA, Wiley JA, Gigliotti F, Harmsen AG. Protection against Pneumocystis carinii pneumonia by antibodies generated from either T helper 1 or T helper 2 responses. Infect Immun 1997;65:5052–6. [6] Oppmann B, Lesley R, Blom B, Timans J, Xu Y, Hunte 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 2000;13:715–25.
404
Editorial / Cytokine & Growth Factor Reviews 21 (2010) 403–404
[7] Infante-Duarte C, Horton HF, Byrne MC, Kamradt T. Microbial lipopeptides induce the production of IL-17 in Th cells. J Immunol 2000;165:6107–15. [8] Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005;6:1133–41. [9] Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, 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 2005;6: 1123–32. [10] Annunziato F, Cosmi L, Romagnani S. Human and murine Th17. Curr Opin HIV AIDS 2010;5:114–9. [11] Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 2003;198:1951–7. [12] Khader SA, Gaffen SL, Kolls JK. Th17 cells at the crossroads of innate and adaptive immunity against infectious diseases at the mucosa. Mucosal Immunol 2009;2:403–11.
Shabaana A. Khader* Division of Infectious Diseases, Department of Pediatrics, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States *Tel.: +1 412 692 7767; fax: +1 412 692 7636 E-mail address: [email protected] Available online 12 November 2010