Generation of IL-23 Producing Dendritic Cells (DCs) by Airborne Fungi Regulates Fungal Pathogenicity via the Induction of TH-17 Responses Georgios Chamilos1,2, Dipyaman Ganguly1, Roberto Lande1, Josh Gregorio1, Stephan Meller1, William E. Goldman4, Michel Gilliet1,3*, Dimitrios P. Kontoyiannis2* 1 Department of Immunology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America, 2 Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America, 3 Department of Melanoma Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America, 4 Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America Abstract Interleukin-17 (IL-17) producing T helper cells (TH-17) comprise a newly recognized T cell subset with an emerging role in adaptive immunity to a variety of fungi. Whether different airborne fungi trigger a common signaling pathway for TH-17 induction, and whether this ability is related to the inherent pathogenic behavior of each fungus is currently unknown. Here we show that, as opposed to primary pathogenic fungi (Histoplasma capsulatum), opportunistic fungal pathogens (Aspergillus and Rhizopus) trigger a common innate sensing pathway in human dendritic cells (DCs) that results in robust production of IL-23 and drives TH-17 responses. This response requires activation of dectin-1 by the fungal cell wall polysaccharide b-glucan that is selectively exposed during the invasive growth of opportunistic fungi. Notably, unmasking of b-glucan in the cell wall of a mutant of Histoplasma not only abrogates the pathogenicity of this fungus, but also triggers the induction of IL-23 producing DCs. Thus, b-glucan exposure in the fungal cell wall is essential for the induction of IL-23/ TH-17 axis and may represent a key factor that regulates protective immunity to opportunistic but not pathogenic fungi. Citation: Chamilos G, Ganguly D, Lande R, Gregorio J, Meller S, et al. (2010) Generation of IL-23 Producing Dendritic Cells (DCs) by Airborne Fungi Regulates Fungal Pathogenicity via the Induction of TH-17 Responses. PLoS ONE 5(9): e12955. doi:10.1371/journal.pone.0012955 Editor: Eleftherios Mylonakis, Massachusetts General Hospital, United States of America Received May 4, 2010; Accepted August 31, 2010; Published September 23, 2010 Copyright: 2010 Chamilos et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by a grant of the DANA Foundation (to M.G.), the M.D. Anderson Cancer Center Core Grant (CA16672) from the University of Texas (to D.P.K.), and the N.I.H. research grant AI25584 (to W.E.G.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: mgilliet@mdanderson.org (MG); dkontoyi@mdanderson.org (DPK) Introduction In recent years, opportunistic fungal pathogens have become major causes of life-threatening infections in an expanding population of severely immunocompromised individuals, as a result of the increasing use of transplantation, the development of immunosuppressive therapies for autoimmune and neoplastic diseases, and the AIDS pandemic [1,2]. In these patients, Aspergillus is the predominant fungal pathogen [3], whereas Zygomycetes have emerged as the second most common cause of opportunistic mold infections [4,5]. Infections caused by these fungi have a poor prognosis with mortality rates exceeding 90% upon dissemination, mainly because of their inherent resistance to existing antifungal agents [1–5]. Thus, there is a need for better understanding of the pathogenesis of opportunistic fungal infections in order to develop novel therapeutic strategies. T helper (TH) cells play a crucial role in host defense against fungi through the secretion of distinct cytokine profiles [6,7]. Traditionally, responses by interferon-c (IFN-c)–producing TH-1 cells are considered to confer protective immunity against fungi, whereas TH-2 responses mediated by IL-4 lead to increased susceptibility to fungal infections [6,7]. More recently, a subset of TH cells, called IL-17-producing TH (TH-17) cells, have been identified and implicated in mucosal immunity against extracel- lular bacteria [8,9] and fungi [10-17]. In particular, IL-17 receptor deficient mice are susceptible to disseminated [10] and oropha- ryngeal [11] candidiasis, whereas impaired IL-17 production has been associated with increased susceptibility to fungal pneumonia caused by Pneumocystis [12], Cryptococcus [13], and Aspergillus ([14]. In humans, patients with mutations in STAT3 have selective impairment of IL-17 producing T cells and are prone to infections with invasive fungal pathogens, including Candida and Aspergillus [15]. Furthermore, Candida-specific human memory CD4+ T cells belong to the TH-17 subset [16], and are significantly decreased in patients with chronic mucocutaneous candidiasis [17]. IL-23, a member of the IL-12 cytokine family, has a master role in regulating TH-17 development [8,9,18]. Dendritic cells (DCs) are the main source of IL-23, which is secreted as a heterodimer comprising of a p19 subunit and a p40 subunit shared with IL-12 [18]. Human TH-17 cells originate from CD161+ T-cell precursors that constitutively express IL-23R [19], and na¨ıve CD4+ T cells differentiate in vitro into mature TH-17 cells in response to the combined activity of IL-23 and IL-1b in the presence of TGF-b [19–22]. In contrast to IL-23, IL-12 is associated with the differentiation of na¨ıve CD4+ T cell into IFN-c secreting TH-1 cells [8,9,18]. PLoS ONE | www.plosone.org 1 September 2010 | Volume 5 | Issue 9 | e12955