Human NK Cells Display Important Antifungal Activity against<i>Aspergillus fumigatus</i>, Which Is Directly Mediated by IFN-γ Release

Bouzani, Maria; Ok, Michael; Mj, Allison; Ebel, Frank; Kurzai, Oliver; Morton, Oliver; Einsele, Hermann; Loeffler, Juergen

doi:10.4049/jimmunol.1003593

Cited by 113 publications

(122 citation statements)

References 43 publications

Supporting

Mentioning

108

Contrasting

Unclassified

Order By: Relevance

“…Half of the IFN-g + cells were CD4 + cells, whereas the rest of the IFN-g + cells were negative for this Th cell marker. We were able to demonstrate that a significant number of NK cells express IFN-g, which is in line with a previous report that demonstrated that NK cells play an important role in the antifungal response to A. fumigatus by releasing IFN-g (43). However, in contrast to this, depletion of CD56 + cells did not alter Aspergillus-induced IFN-g responses.…”

Section: Discussionsupporting

confidence: 69%

Aspergillus fumigatus–Induced IL-22 Is Not Restricted to a Specific Th Cell Subset and Is Dependent on Complement Receptor 3

Gresnigt

Becker

Smeekens

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

Th cell responses induced by Aspergillus fumigatus have been extensively investigated in mouse models. However, the requirements for differentiation and the characteristics of A. fumigatus–induced human Th cell subsets remain poorly defined. We demonstrate that A. fumigatus induces Th1 and Th17 subsets in human PBMCs. Moreover, we show that the cytokine IL-22 is not restricted to a specific Th subset, in contrast to IL-17A. The pattern recognition and cytokine pathways that skew these Aspergillus-induced Th cell responses are TLR4- and IL-1–, IL-23–, and TNF-α–dependent. These pathways are of specific importance for production of the cytokines IL-17A and IL-22. Additionally, our data reveal that the dectin-1/Syk pathway is redundant and that TLR2 has an inhibitory effect on Aspergillus-induced IL-17A and IL-22 production. Notably, blocking complement receptor (CR)3 significantly reduced Aspergillus-induced Th1 and Th17 responses, and this was independent on the activation of the complement system. CR3 is a known receptor for β-1,3-glucan; however, blocking CR3 had significant effects on Th cell responses induced by heat-killed Aspergillus conidia, which have minimal β-glucan expression on their cell surface. Collectively, these data characterize the human Th cell subsets induced by Aspergillus, demonstrate that the capability to produce IL-22 is not restricted to a specific T cell subset, and provide evidence that CR3 might play a significant role in the adaptive host defense against Aspergillus, although the ligand and its action remain to be elucidated.

show abstract

Section: Discussionsupporting

confidence: 69%

Aspergillus fumigatus–Induced IL-22 Is Not Restricted to a Specific Th Cell Subset and Is Dependent on Complement Receptor 3

Gresnigt

Becker

Smeekens

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…No studies have previously assessed the impact of the inflammasome on the Th1 defense mechanisms during PCM. Because IFN-g is an important cytokine involved in the resistance to P. brasiliensis and other several fungi (11,27,(44)(45)(46)(47)(48)(49)(50), we speculated that IFN-g could play a role in the central mechanism regulated by caspase-1 after P. brasiliensis infection. Confirming this hypothesis, IFN-g production and the Th1 response were lower in infected Asc 2/2 , Casp1 2/2 , and Nlrp3 mice were susceptible to experimental PCM because they exhibited reduced Th1 (and not Th17) immunity.…”

Section: Discussionmentioning

confidence: 99%

IL-18 Triggered by the Nlrp3 Inflammasome Induces Host Innate Resistance in a Pulmonary Model of Fungal Infection

Ketelut-Carneiro

Silva

Rocha

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Pathogens are sensed by innate immune receptors that initiate an efficient adaptive immune response upon activation. The elements of the innate immune recognition process for Paracoccidioides brasiliensis include TLR-2, TLR-4, and dectin-1. However, there are additional receptors necessary for the host immune responses to P. brasiliensis. The nucleotide-binding oligomerization domain–like receptor (NLRs), which activate inflammasomes, are candidate receptors that deserve renewed investigation. After pathogen infection, the NLRs form large signaling platforms called inflammasomes, which lead to caspase-1 activation and maturation of proinflammatory cytokines (IL-18 and IL-1β). In this study, we showed that NLR family pyrin domain–containing 3 (Nlrp3) is required to induce caspase-1 activation and further secretion of IL-1β and IL-18 by P. brasiliensis–infected macrophages. Additionally, potassium efflux and lysosomal acidification induced by the fungus were important steps in the caspase-1 activation mechanism. Notably, Nlrp3 and caspase-1 knockout mice were more susceptible to infection than were the wild-type animals, suggesting that the Nlrp3-dependent inflammasomes contribute to host protection against P. brasiliensis. This protective effect occurred owing to the inflammatory response mediated by IL-18, as shown by an augmented fungus burden in IL-18 knockout mice. Taken together, our results show that the Nlrp3 inflammasome is essential for resistance against P. brasiliensis because it orchestrates robust caspase-1 activation and triggers an IL-18–dependent proinflammatory response.

show abstract

“…The exocytosis of cytolytic granules apparently can disrupt fungal germination directly, as evident from the reports that granzyme-deficient mice are susceptible to IFI (41,42). The production of IFN-γ from the D-CAR + T cells may further augment immunity to IFIs, because pharmacological dosing of recombinant IFN-γ (43) or of IFN-γ derived from CD4 + helper T cells or NK cells has been shown to augment anti-Aspergillus activity (44,45). However, it remains to be determined whether the D-CAR-dependent production of IFN-γ can contribute directly to the clearance of fungal infections or indirectly through the activation of granulocytes.…”

Section: Discussionmentioning

confidence: 89%

Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection

Kumaresan

Manuri

Albert

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

182

121

View full text Add to dashboard Cite

Significance Patients with compromised T-cell function are at risk for opportunistic fungal infections. We have developed a novel approach to restore immunity by using a fungal pattern-recognition receptor Dectin-1 to redirect T-cell specificity to carbohydrate antigen in the fungal cell wall. We did so by genetically modifying T cells using the nonviral Sleeping Beauty gene-transfer system to enforce expression of a chimeric antigen receptor (CAR) that recapitulates the specificity of Dectin-1 (D-CAR). The D-CAR + T cells can be electroporated and propagated on artificial activating and propagating cells in a manner suitable for human application, enabling this immunology to be translated into immunotherapy. This approach has implications for genetically modifying T cells to express CARs with specificity for carbohydrate and thus broadening their application in the investigational treatment of pathogens and malignancies.

show abstract

Human NK Cells Display Important Antifungal Activity againstAspergillus fumigatus, Which Is Directly Mediated by IFN-γ Release

Cited by 113 publications

References 43 publications

Aspergillus fumigatus–Induced IL-22 Is Not Restricted to a Specific Th Cell Subset and Is Dependent on Complement Receptor 3

Aspergillus fumigatus–Induced IL-22 Is Not Restricted to a Specific Th Cell Subset and Is Dependent on Complement Receptor 3

IL-18 Triggered by the Nlrp3 Inflammasome Induces Host Innate Resistance in a Pulmonary Model of Fungal Infection

Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection

Contact Info

Product

Resources

About