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TH17 Cells in Fungal Infections

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TH17 Cells in Health and Disease

Abstract

Although TH1 responses driven by the IL-12/IFN-gamma axis are central to protection against fungi, the paradigm has been revisited with two new T cell populations entering the scene: the TH17 cells involved in inflammatory responses, and the T regulatory cells (Tregs), which minimize immune responses to avoid damage to the host. While many studies have focused on the pathological aspects of IL-17-producing T cells in many auto-immune diseases, their role in protective anti-microbial immunity has also been increasingly recognized. Some degree of inflammation is required for protection, particularly in mucosal tissues during the transitional response occurring between the rapid innate and slower adaptive response. However, progressive inflammation worsens disease, limits protective antifungal immune responses and ultimately prevents pathogen eradication. In this scenario, deregulated activity of TH17 cells and Tregs in mediating and restraining inflammation may occur. The enzyme indoleamine 2, 3-dioxygenase and tryptophan metabolites crucially contribute to immune homeostasis by limiting TH17 cell activation and inducing Tregs-taming heightened inflammatory responses. The new findings support a view in which the immune system tailors protective responses to suit infecting fungi while limiting host damage through distinct modules of immunity.

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References

  • Acosta-Rodriguez EV, Napolitani G et al. (2007). Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 8: 942–949.

    Article  PubMed  CAS  Google Scholar 

  • Armstrong-James DP, Turnbull SA et al. (2009). Impaired interferon-gamma responses, increased interleukin-17 expression, and a tumor necrosis factor-alpha transcriptional program in invasive aspergillosis. J Infect Dis 200: 1341–1351.

    Article  PubMed  CAS  Google Scholar 

  • Aujla SJ, Chan YR et al. (2008). IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med 14: 275–281.

    Article  PubMed  CAS  Google Scholar 

  • Bach JF (2002). The effect of infections on susceptibility to auto-immune and allergic diseases. N Engl J Med 347: 911–920.

    Article  PubMed  Google Scholar 

  • Bonifazi P, D’Angelo C et al. (2010). Intranasally delivered siRNA targeting PI3K/Akt/mTOR inflammatory pathways protects from aspergillosis. Mucosal Immunol 3: 193–205.

    Article  PubMed  CAS  Google Scholar 

  • Bonifazi P, Zelante T et al (2009). Balancing inflammation and tolerance in vivo through dendritic cells by the commensal Candida albicans. Mucosal Immunol 2: 362–374.

    Article  PubMed  CAS  Google Scholar 

  • Bozza S, Clavaud C et al. (2009). Immune Sensing of Aspergillus fumigatus Proteins, Glycolipids, and Polysaccharides and the Impact on Th Immunity and Vaccination. J Immunol 183: 2407–2414.

    Article  PubMed  CAS  Google Scholar 

  • Cavassani KA, Campanelli AP et al. (2006). Systemic and local characterization of regulatory T cells in a chronic fungal infection in humans. J Immunol 177: 5811–5818.

    Google Scholar 

  • Chai LY, van de Veerdonk F et al. (2010). Anti-Aspergillus human host defence relies on type 1 T helper (Th1), rather than type 17 T helper (Th17), cellular immunity. Immunology 130: 46–54.

    Article  PubMed  CAS  Google Scholar 

  • Conti HR, Shen F et al (2009). Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J Exp Med 206: 299–311.

    Article  PubMed  CAS  Google Scholar 

  • Corvino CL, Mamoni RL et al. (2007). Serum interleukin-18 and soluble tumour necrosis factor receptor 2 are associated with disease severity in patients with paracoccidioidomycosis. Clin Exp Immunol 147: 483–490.

    Article  PubMed  CAS  Google Scholar 

  • De Luca A, Montagnoli C et al. (2007). Functional yet balanced reactivity to Candida albicans requires TRIF, MyD88, and IDO-dependent inhibition of Rorc. J Immunol 179: 5999–6008.

    PubMed  Google Scholar 

  • De Luca A, Zelante T et al. (2010). IL-22 defines a novel developmental pathway of antifungal resistance. Mucosal Immunol 3: 361–73.

    Article  PubMed  Google Scholar 

  • Deepe GS Jr. and Gibbons RS (2008). TNF-alpha antagonism generates a population of antigen-specific CD4  +  CD25+ T cells that inhibit protective immunity in murine histoplasmosis. J Immunol 180: 1088–1097.

    PubMed  CAS  Google Scholar 

  • Dong C (2008). TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol 8: 337–348.

    Article  PubMed  CAS  Google Scholar 

  • Eyerich K, Rombold S et al. (2007). Altered, but not diminished specific T cell response in chronic mucocutaneous candidiasis patients. Arch Dermatol Res 299: 475–481.

    Article  PubMed  CAS  Google Scholar 

  • Fenoglio D, Poggi A et al. (2009). Vdelta1 T lymphocytes producing IFN-gamma and IL-17 are expanded in HIV-1-infected patients and respond to Candida albicans. Blood 113: 6611–6618.

    Article  PubMed  CAS  Google Scholar 

  • Ferwerda B, Ferwerda G et al. (2009). Human dectin-1 deficiency and mucocutaneous fungal infections. N Engl J Med 361: 1760–1767.

    Article  PubMed  CAS  Google Scholar 

  • Grohmann U, Fallarino F et al. (2003). Tolerance, DCs and tryptophan: much ado about IDO. Trends Immunol 24: 242–248.

    Article  PubMed  CAS  Google Scholar 

  • Grohmann U, Volpi C et al. (2007). Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Nat Med 13: 579–586.

    Article  PubMed  CAS  Google Scholar 

  • Heninger E, Hogan LH et al. (2006). Characterization of the Histoplasma capsulatum-induced granuloma. J Immunol 177: 3303–3313.

    PubMed  CAS  Google Scholar 

  • Hirota K, Martin B et al. (2010). Development, regulation and functional capacities of Th17 cells. Semin Immunopathol 32: 3–16.

    Article  PubMed  CAS  Google Scholar 

  • Holland SM, DeLeo FR et al. (2007). STAT3 mutations in the hyper-IgE syndrome. N Engl J Med 357: 1608–1619.

    Article  PubMed  CAS  Google Scholar 

  • Hori S, Carvalho TL et al. (2002). CD25  +  CD4+ regulatory T cells suppress CD4+ T cell-mediated pulmonary hyperinflammation driven by Pneumocystis carinii in immuno-deficient mice. Eur J Immunol 32: 1282–1291.

    Article  PubMed  CAS  Google Scholar 

  • Huang W, Na L et al. (2004). Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J Infect Dis 190: 624–631.

    Article  PubMed  CAS  Google Scholar 

  • Kivity S, Agmon-Levin N et al. (2009). Infections and auto-immunity–friends or foes? Trends Immunol 30: 409–414.

    Article  PubMed  CAS  Google Scholar 

  • Kleinschek MA, Muller U et al. (2006). IL-23 enhances the inflammatory cell response in Cryptococcus neoformans infection and induces a cytokine pattern distinct from IL-12. J Immunol 176: 1098–1106.

    PubMed  CAS  Google Scholar 

  • Kolls JK, McCray PB Jr et al. (2008). Cytokine-mediated regulation of antimicrobial proteins. Nat Rev Immunol 8: 829–835.

    Article  PubMed  CAS  Google Scholar 

  • Korn T, Bettelli E et al. (2009). IL-17 and Th17 Cells. Annu Rev Immunol 27: 485–517.

    Article  PubMed  CAS  Google Scholar 

  • Laurence A, O’Shea JJ et al. (2008). Interleukin-22: a sheep in wolf’s clothing. Nat Med 14: 247–249.

    Article  PubMed  CAS  Google Scholar 

  • Lazar-Molnar E, Gacser A et al. (2008). The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus Histoplasma capsulatum. Proc Natl Acad Sci USA 105: 2658–2663.

    Article  PubMed  CAS  Google Scholar 

  • Leibundgut-Landmann S, Gross O et al. (2007). Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat Immunol 8: 630–638.

    Article  PubMed  CAS  Google Scholar 

  • Levin NA (2009). Beyond spaghetti and meatballs: skin diseases associated with the Malassezia yeasts. Dermatol Nurs 21: 7–13, 51; quiz 14.

    Google Scholar 

  • Lilic D (2002). New perspectives on the immunology of chronic mucocutaneous candidiasis. Curr Opin Infect Dis 15: 143–147.

    Article  PubMed  Google Scholar 

  • Lin L, Ibrahim AS et al. (2009). Th1-Th17 cells mediate protective adaptive immunity against Staphylococcus aureus and Candida albicans infection in mice. PLoS Pathog 5: e1000703.

    Article  PubMed  Google Scholar 

  • Lin Y, Ritchea S et al. (2009). Interleukin-17 is required for T helper 1 cell immunity and host resistance to the intracellular pathogen Francisella tularensis. Immunity 31: 799–810.

    Article  PubMed  CAS  Google Scholar 

  • Littman DR and Rudensky AY (2010) Th17 and regulatory T cells in mediating and restraining inflammation. Cell 140: 845–858.

    Article  PubMed  CAS  Google Scholar 

  • Liu Y, Yang B et al. (2009). Memory IL-22-producing CD4+ T cells specific for Candida albicans are present in humans. Eur J Immunol 39: 1472–1479.

    Article  PubMed  CAS  Google Scholar 

  • Loures FV, Pina A et al. (2010). Toll-like receptor 4 signaling leads to severe fungal infection associated with enhanced pro-inflammatory immunity and impaired expansion of regulatory T cells. Infect Immun 78: 1078–1088.

    Article  PubMed  CAS  Google Scholar 

  • Ma HL, Liang S et al. (2008). IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation. J Clin Invest 118: 597–607.

    PubMed  CAS  Google Scholar 

  • McGeachy MJ, Chen Y et al. (2009). The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol 10: 314–324.

    Article  PubMed  CAS  Google Scholar 

  • McKinley L, Logar AJ et al. (2006). Regulatory T cells dampen pulmonary inflammation and lung injury in an animal model of pneumocystis pneumonia. J Immunol 177: 6215–626.

    PubMed  CAS  Google Scholar 

  • Mellor AL and Munn DH (2004). IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4: 762–774.

    Article  PubMed  CAS  Google Scholar 

  • Milner JD, Brenchley JM et al. (2008). Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452: 773–776.

    Article  PubMed  CAS  Google Scholar 

  • Miossec P, Korn T et al. (2009). Interleukin-17 and type 17 helper T cells. N Engl J Med 361: 888–898.

    Article  PubMed  CAS  Google Scholar 

  • Montagnoli C, Bacci A et al. (2002). B7/CD28-dependent CD4  +  CD25+ regulatory T cells are essential components of the memory-protective immunity to Candida albicans. J Immunol 169: 6298–6308.

    PubMed  CAS  Google Scholar 

  • Montagnoli C, Fallarino F et al. (2006). Immunity and tolerance to Aspergillus involve functionally distinct regulatory T cells and tryptophan catabolism. J Immunol 176: 1712–1723.

    PubMed  CAS  Google Scholar 

  • Moreira, A. P., K. A. Cavassani, et al. (2008). CCR5-dependent regulatory T cell migration mediates fungal survival and severe immuno-suppression. J Immunol 180: 3049–3056.

    PubMed  CAS  Google Scholar 

  • Netea MG, Kullberg BJ et al. (2005). Severely impaired IL-12/IL-18/IFNgamma axis in patients with hyper IgE syndrome. Eur J Clin Invest 35: 718–721.

    Article  PubMed  CAS  Google Scholar 

  • O’Garra A and Vieira P (2004). Regulatory T cells and mechanisms of immune system control. Nat Med 10: 801–805.

    Article  PubMed  Google Scholar 

  • Rizzetto L, Kuka M et al. (2010). Differential IL-17 production and mannan recognition contribute to fungal pathogenicity and commensalism. J Immunol 184: 4258–4268.

    Article  PubMed  CAS  Google Scholar 

  • Romagnani S, Maggi E et al. (2009). Properties and origin of human Th17 cells. Mol Immunol 47:3–7.

    Article  PubMed  CAS  Google Scholar 

  • Romani L (2001). Overview of the fungal pathogens. Immunology of Infectious Diseases. S. H. E. Kaufman, A. Sher and R. Ahmed. Washington D.C., ASM Press: 25–37.

    Google Scholar 

  • Romani L (2004). Immunity to fungal infections. Nat Rev Immunol 4: 1–23.

    Article  PubMed  Google Scholar 

  • Romani L (2008a). Cell mediated immunity to fungi: a reassessment. Med Mycol 46: 515–529.

    Article  PubMed  CAS  Google Scholar 

  • Romani L (2008b). Parasites and auto-immunity: the case of fungi. Autoimmun Rev 8: 129–133.

    Article  PubMed  CAS  Google Scholar 

  • Romani L, Fallarino F et al. (2008a). Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease. Nature 451: 211–215.

    Article  PubMed  CAS  Google Scholar 

  • Romani L and Puccetti P (2006). Protective tolerance to fungi: the role of IL-10 and tryptophan catabolism. Trends Microbiol 14: 183–189.

    Article  PubMed  CAS  Google Scholar 

  • Romani L and Puccetti P (2007). Controlling pathogenic inflammation to fungi. Expert Rev Anti Infect Ther 5: 1007–1017.

    Article  PubMed  CAS  Google Scholar 

  • Romani L and Puccetti P (2008b). Immune regulation and tolerance to fungi in the lungs and skin. Chem Immunol Allergy 94: 124–137.

    Article  PubMed  CAS  Google Scholar 

  • Romani L, Zelante T et al. (2008b). IL-17 and therapeutic kynurenines in pathogenic inflammation to fungi. J Immunol 180: 5157–5162.

    PubMed  CAS  Google Scholar 

  • Ryan KR, Lawson CA et al. (2005). CD4  +  CD25+ T-regulatory cells are decreased in patients with auto-immune polyendocrinopathy candidiasis ectodermal dystrophy. J Allergy Clin Immunol 116: 1158–1159.

    Article  PubMed  CAS  Google Scholar 

  • Schneider DS and Ayres JS (2008). Two ways to survive infection: what resistance and tolerance can teach us about treating infectious diseases. Nat Rev Immunol 8: 889–895.

    Article  PubMed  CAS  Google Scholar 

  • Schulz SM, Kohler G et al. (2008). Protective immunity to systemic infection with attenuated Salmonella enterica serovar enteritidis in the absence of IL-12 is associated with IL-23-dependent IL-22, but not IL-17. J Immunol 181: 7891–7901.

    PubMed  CAS  Google Scholar 

  • Shoham S and Levitz SM (2005). The immune response to fungal infections. Br J Haematol 129: 569–582.

    Article  PubMed  Google Scholar 

  • Singh N and Perfect JR (2007). Immune reconstitution syndrome associated with opportunistic mycoses. Lancet Infect Dis 7: 395–401.

    Article  PubMed  Google Scholar 

  • Sundrud MS, Koralov SB et al. (2009). Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science 324: 1334–1338.

    Article  PubMed  CAS  Google Scholar 

  • van de Veerdonk FL, Marijnissen R et al. (2010). Milder clinical hyperimmunoglobulin E syndrome phenotype is associated with partial interleukin-17 deficiency. Clin Exp Immunol 159: 57–64.

    Article  PubMed  Google Scholar 

  • van de Veerdonk FL, Marijnissen RJ et al. (2009). The macrophage mannose receptor induces IL-17 in response to Candida albicans. Cell Host Microbe 5: 329–340.

    Article  PubMed  Google Scholar 

  • Vivier E, Spits H et al. (2009). Interleukin-22-producing innate immune cells: new players in mucosal immunity and tissue repair? Nat Rev Immunol 9: 229–234.

    Article  PubMed  CAS  Google Scholar 

  • Xu T, Logsdon NJ et al. (2005). Structure of insect-cell-derived IL-22. Acta Crystallogr D Biol Crystallogr 61: 942–950.

    Article  PubMed  Google Scholar 

  • Zelante T, De Luca A et al. (2007). IL-23 and the Th17 pathway promote inflammation and impair anti-fungal immune resistance. Eur J Immunol 37: 2695–2706.

    Article  PubMed  CAS  Google Scholar 

  • Zelante T, De Luca A et al. (2009a). IL-17/Th17 in anti-fungal immunity: what’s new? Eur J Immunol 39: 645–648.

    Article  PubMed  CAS  Google Scholar 

  • Zelante T, Fallarino F et al. (2009b). Indoleamine 2,3-dioxygenase in infection: the paradox of an evasive strategy that benefits the host. Microbes Infect 11: 133–141.

    Article  PubMed  CAS  Google Scholar 

  • Zenewicz LA and Flavell RA (2008). IL-22 and inflammation: leukin’ through a glass onion. Eur J Immunol 38: 3265–3268.

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y, Wang F et al. (2009). Robust Th1 and Th17 immunity supports pulmonary clearance but cannot prevent systemic dissemination of highly virulent Cryptococcus neoformans H99. Am J Pathol 175: 2489–2500.

    Article  PubMed  CAS  Google Scholar 

  • Zheng Y, Valdez PA et al. (2008). Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med 14: 282–289.

    Article  PubMed  CAS  Google Scholar 

  • Zhou L, Chong MM et al. (2009). Plasticity of CD4+ T cell lineage differentiation. Immunity 30: 646–655.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by the Specific Targeted Research Project “ALLFUN” (FP7-HEALTH-2009) and the Italian project PRIN prot.2007KLCKP8_004.

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Authors and Affiliations

  1. Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, Perugia, 06122, Italy

    Luigina Romani

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  1. Teresa Zelante
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  2. Antonella De Luca
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  3. Luigina Romani
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Correspondence to Luigina Romani .

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Editors and Affiliations

  1. King's College London, Department of Nephrology and Transplanta, Guy's Hospital, London, WC2R 2LS, United Kingdom

    Shuiping Jiang

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Zelante, T., De Luca, A., Romani, L. (2011). TH17 Cells in Fungal Infections. In: Jiang, S. (eds) TH17 Cells in Health and Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9371-7_16

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