Rethinking T cell immunity in oropharyngeal candidiasis

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Abstract

The disproportionate increase in oropharyngeal candidiasis (OPC) compared with systemic and vaginal candidiasis in female patients with AIDS has been a paradox for almost three decades. New data now show that severe OPC develops in Th17-deficient mice, but not Th1-deficient mice, implicating Th17-induced effector molecules in resistance to oral disease. These findings clarify and extend our current thinking about how CD4 T cell deficiency influences susceptibility to OPC.

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Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis

Heather Conti, Fang-Fang Shen, Namrata Nayyar … (2009)

The commensal fungus Candida albicans causes oropharyngeal candidiasis (OPC; thrush) in settings of immunodeficiency. Although disseminated, vaginal, and oral candidiasis are all caused by C. albicans species, host defense against C. albicans varies by anatomical location. T helper 1 (Th1) cells have long been implicated in defense against candidiasis, whereas the role of Th17 cells remains controversial. IL-17 mediates inflammatory pathology in a gastric model of mucosal candidiasis, but is host protective in disseminated disease. Here, we directly compared Th1 and Th17 function in a model of OPC. Th17-deficient (IL-23p19−/−) and IL-17R–deficient (IL-17RA−/−) mice experienced severe OPC, whereas Th1-deficient (IL-12p35−/−) mice showed low fungal burdens and no overt disease. Neutrophil recruitment was impaired in IL-23p19−/− and IL-17RA−/−, but not IL-12−/−, mice, and TCR-αβ cells were more important than TCR-γδ cells. Surprisingly, mice deficient in the Th17 cytokine IL-22 were only mildly susceptible to OPC, indicating that IL-17 rather than IL-22 is vital in defense against oral candidiasis. Gene profiling of oral mucosal tissue showed strong induction of Th17 signature genes, including CXC chemokines and β defensin-3. Saliva from Th17-deficient, but not Th1-deficient, mice exhibited reduced candidacidal activity. Thus, the Th17 lineage, acting largely through IL-17, confers the dominant response to oral candidiasis through neutrophils and antimicrobial factors.

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Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice.

Weitao Huang, Li Na, Paul Fidel … (2004)

T cells are required for normal host defense against fungal infection, and individuals with T cell-deficiency syndromes are highly susceptible to fungal pathogens. Interleukin (IL)-17A is a proinflammatory cytokine that interconnects myeloid and lymphoid host defense. The role of murine (m) IL-17A/mIL-17A receptor (R) interactions was evaluated in a murine model of systemic candidiasis. In response to systemic challenge with Candida albicans, expression of mIL-17A was induced, and IL-17AR knockout (IL-17AR(-/-)) mice had dose-dependent, substantially reduced survival. Fungal burden in the kidneys of IL-17AR(-/-) mice was dramatically increased (25-fold at 96 h). In IL-17AR(-/-) mice, both mobilization of peripheral neutrophils and their influx to infected organs were significantly impaired and delayed. In vivo expression of mIL-17A protected normal mice from a lethal dose of C. albicans (100% at day 7 and 65% at day 42). The data suggest that the mIL-17A/mIL-17AR system is required for normal fungal host defense in vivo. IL-17A could have potential as a therapeutic cytokine for systemic C. albicans infections in immunocompromised patients with cancer or advanced acquired immunodeficiency syndrome.

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Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae

Kyle I. Happel, Patricia Dubin, Mingquan Zheng … (2005)

Interleukin (IL)-23 is a heterodimeric cytokine that shares the identical p40 subunit as IL-12 but exhibits a unique p19 subunit similar to IL-12 p35. IL-12/23 p40, interferon γ (IFN-γ), and IL-17 are critical for host defense against Klebsiella pneumoniae. In vitro, K. pneumoniae–pulsed dendritic cell culture supernatants elicit T cell IL-17 production in a IL-23–dependent manner. However, the importance of IL-23 during in vivo pulmonary challenge is unknown. We show that IL-12/23 p40–deficient mice are exquisitely sensitive to intrapulmonary K. pneumoniae inoculation and that IL-23 p19 −/− , IL-17R −/− , and IL-12 p35 −/− mice also show increased susceptibility to infection. p40 −/− mice fail to generate pulmonary IFN-γ, IL-17, or IL-17F responses to infection, whereas p35 −/− mice show normal IL-17 and IL-17F induction but reduced IFN-γ. Lung IL-17 and IL-17F production in p19 −/− mice was dramatically reduced, and this strain showed substantial mortality from a sublethal dose of bacteria (103 CFU), despite normal IFN-γ induction. Administration of IL-17 restored bacterial control in p19 −/− mice and to a lesser degree in p40 −/− mice, suggesting an additional host defense requirement for IFN-γ in this strain. Together, these data demonstrate independent requirements for IL-12 and IL-23 in pulmonary host defense against K. pneumoniae, the former of which is required for IFN-γ expression and the latter of which is required for IL-17 production.

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Journal

Journal ID (nlm-ta): J Exp Med

Journal ID (iso-abbrev): J. Exp. Med

Journal ID (hwp): jem

Title: The Journal of Experimental Medicine

Publisher: The Rockefeller University Press

ISSN (Print): 0022-1007

ISSN (Electronic): 1540-9538

Publication date (Print): 16 February 2009

Volume: 206

Issue: 2

Pages: 269-273

Affiliations

L.P. and A.C. are at the Departments of Medicine and Microbiology and Immunology of the Albert Einstein College of Medicine College of Medicine, Bronx, NY

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CORRESPONDENCE A.C.: casadeva@ 123456aecom.yu.edu

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Publisher ID: 20090093

DOI: 10.1084/jem.20090093

PMC ID: 2646576

PubMed ID: 19204107

SO-VID: b736a866-f8b3-483c-9955-167c4d8a9b3f

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This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

Rethinking T cell immunity in oropharyngeal candidiasis

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Gamma Delta T cells

Most cited references 29

Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis

Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice.

Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae

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