Absence of Foxp3+ Regulatory T Cells during Allergen Provocation Does Not Exacerbate Murine Allergic Airway Inflammation

Baru, Abdul Mannan; Ganesh, Venkateswaran; Krishnaswamy, Jayendra Kumar; Hesse, Christina; Untucht, Christopher; Glage, Silke; Behrens, Georg M. N.; Mayer, Christian T.; Puttur, Franz; Sparwasser, Tim

doi:10.1371/journal.pone.0047102

Cited by 18 publications

(18 citation statements)

References 41 publications

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“…The role of Treg cells during allergen-induced airway inflammation has previously been examined. Utilizing BAC-transgenic Foxp3.DTR (DEREG) mice, Baru et al reported that the lack of Treg cells during ovalbumin antigen challenge does not aggravate allergic airway inflammation (25). We tested the roles of Treg cells during CA-induced eosinophilic inflammation using Foxp3.DTR knockin mice (26).…”

Section: Resultsmentioning

confidence: 99%

Lung-Infiltrating Foxp3+ Regulatory T Cells Are Quantitatively and Qualitatively Different during Eosinophilic and Neutrophilic Allergic Airway Inflammation but Essential To Control the Inflammation

Jang

Nguyen

Kim

et al. 2017

The Journal of Immunology

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Understanding functions of Foxp3+ regulatory T (Treg) cells during allergic airway inflammation remains incomplete. In this study, we report that during cockroach antigen (CA)-induced allergic airway inflammation Foxp3+ Treg cells are rapidly mobilized into the inflamed lung tissues. However, the level of Treg cell accumulation in the lung was different depending on the type of inflammation. During eosinophilic airway inflammation, ~30% of lung infiltrating CD4 T cells express Foxp3, an indicative of Treg cells. On the contrary, only ~10% of infiltrating CD4 T cells express Foxp3 during neutrophilic airway inflammation. Despite the different accumulation, both the lung inflammation and inflammatory T cell responses were aggravated following Treg cell depletion regardless of the type of inflammation, suggesting regulatory roles of Treg cells. Interestingly, however, the extent to which inflammatory responses are aggravated by Treg cell depletion was significantly greater during eosinophilic airway inflammation. Indeed, lung infiltrating Treg cells exhibit phenotypic and functional features associated with potent suppression. Our results demonstrate that Treg cells are essential regulators of inflammation regardless of the type of inflammation, although the mechanisms employed by Treg cells to control inflammation may be shaped by environmental cues available to those Treg cells.

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Section: Resultsmentioning

confidence: 99%

Lung-Infiltrating Foxp3+ Regulatory T Cells Are Quantitatively and Qualitatively Different during Eosinophilic and Neutrophilic Allergic Airway Inflammation but Essential To Control the Inflammation

Jang

Nguyen

Kim

et al. 2017

The Journal of Immunology

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“…Therefore, depletion of Treg cells can be achieved by DT application [51]. As shown elsewhere [32,56] in naïve DEREG mice a subset of FoxP3 + Treg cells lacking the DT receptor and GFP expression is not affected by the treatment. However, for the infection model described here even a few days of almost total ablation of Treg cells leads to a significant alteration of the immune response.…”

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confidence: 80%

CD4⁺FoxP3⁺ regulatory T cells suppress fatal T helper 2 cell immunity during pulmonary fungal infection

et al. 2014

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The opportunistic fungal pathogen Cryptococcus neoformans causes lung inflammation and fatal meningitis in immunocompromised patients. Regulatory T (Treg) cells play an important role in controlling immunity and homeostasis. However, their functional role during fungal infection is largely unknown. In this study, we investigated the role of Treg cells during experimental murine pulmonary C. neoformans infection. We show that the number of CD4 + FoxP3 + Treg cells in the lung increases significantly within the first weeks after intranasal infection of BALB/c wild-type mice. To define the function of Treg cells we used DEREG mice allowing selective depletion of CD+ FoxP3+ Treg cells by application of diphtheria toxin. In Treg cell-depleted mice, stronger pulmonary allergic inflammation with enhanced mucus production and pronounced eosinophilia, increased IgE production, and elevated fungal lung burden were found. This was accompanied by higher frequencies of GATA-3 + T helper (Th) 2 cells with elevated capacity to produce interleukin (IL)-4, IL-5, and IL-13. In contrast, only a mild increase in the Th1-associated immune response unrelated to the fungal infection was observed. In conclusion, the data demonstrate that during fungal infection pulmonary Treg cells are induced and preferentially suppress Th2 cells thereby mediating enhanced fungal control. Keywords: Cryptococcus neoformans r Pulmonary fungal infection r Regulatory T (Treg) cells r Th2 immunityAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionCryptococcus neoformans is a globally distributed, opportunistic fungal pathogen. Primary infection most commonly occurs via inhalation of spores or infectious propagules which encounter alveolar macrophages or dendritic cells in the lung and triggerCorrespondence: Prof. Gottfried Alber e-mail: alber@rz.uni-leipzig.de an immune response [1,2]. In immunocompromised patients, the inability to control the infection by macrophages readily leads to systemic dissemination with subsequent development of fatal meningoencephalitis [3]. As a consequence, cryptococcal meningitis accounts for the majority of worldwide deaths from HIV-related fungal infections [4,5]. It has been well established that the efficient control of C. neoformans requires a T helper cell (Th)1-immune response [6,7]. Mice lacking the Th1-type cytokines interferon-γ (IFN-γ) or interleukin (IL)-12 show a decreased survival rate [8,9].www.eji-journal.eu Eur. J. Immunol. 2014. 44: 3596-3604 Immunity to infection 3597In contrast, the loss of hallmark Th2-type cytokines such as IL-4 and IL-13 (or their common IL-4 receptor) confers protection and promotes survival [10][11][12][13] Results CD4+ FoxP3 + regulatory T cells increase early during pulmonary infection with C. neoformans Experimental pulmonary infection with the opportunistic fungal pathogen C. neoformans revealed a protective role of Th1 and Th17 immunity, while a Th2-biased immune response is detrimental [29]. The role o...

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“…These results are in accordance with our own findings. Furthermore, depletion of Tregs during the sensitization phase can aggravate allergic airway inflammation (Baru et al, 2010), whereas depletion during the challenge phase has no such effect (Baru et al, 2012). Similarly, we could retrace these findings in our own depletion experiments: immunoglobulin responses toward the primary antigen (OVA) were not influenced by depletion of Tregs during the challenge phase (Supplementary Figure S3 online), but depletion of Tregs during EC sensitization with the secondary antigen allowed collateral priming to take place in the skin.…”

Section: Discussionmentioning

confidence: 63%

Superior Suppressive Capacity of Skin Tregs Compared with Lung Tregs in a Model of Epicutaneous Priming

Mahapatra

Albrecht

Baru

et al. 2015

Journal of Investigative Dermatology

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We have previously shown that T helper type 2 (Th2)-polarized airway inflammation can facilitate priming to new antigens in the lungs, which we called "collateral priming". To investigate whether allergic skin inflammation can also facilitate priming toward new antigens, we developed an allergic skin inflammation model based on an allergic lung inflammation model. Mice were sensitized intraperitoneally toward the primary antigen, ovalbumin. Challenge was subsequently performed intranasally or epicutaneously with ovalbumin and a secondary antigen, keyhole limpet hemocyanin (KLH). Re-challenge consisted of local application of either antigen alone. Analysis of KLH-specific antibody responses, KLH-specific cytokines, and local inflammation demonstrated tolerance induction toward the secondary antigen in the skin, whereas in the lung priming had occurred. Flow-cytometric analysis revealed increased numbers of regulatory T cells (Tregs), increased cytotoxic T lymphocyte antigen-4 (CTLA-4) expression, and an enhanced suppressive capacity of Tregs from skin-draining lymph nodes when compared with Tregs from the lung-draining lymph nodes. Furthermore, depletion of Tregs resulted in restoration of collateral priming in the skin. These results demonstrate crucial local differences between the Treg function in the skin and lung to repetitive antigen exposure, which can decisively influence the immune response toward new antigens.

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Absence of Foxp3+ Regulatory T Cells during Allergen Provocation Does Not Exacerbate Murine Allergic Airway Inflammation

Cited by 18 publications

References 41 publications

Lung-Infiltrating Foxp3+ Regulatory T Cells Are Quantitatively and Qualitatively Different during Eosinophilic and Neutrophilic Allergic Airway Inflammation but Essential To Control the Inflammation

Lung-Infiltrating Foxp3+ Regulatory T Cells Are Quantitatively and Qualitatively Different during Eosinophilic and Neutrophilic Allergic Airway Inflammation but Essential To Control the Inflammation

CD4⁺FoxP3⁺ regulatory T cells suppress fatal T helper 2 cell immunity during pulmonary fungal infection

Superior Suppressive Capacity of Skin Tregs Compared with Lung Tregs in a Model of Epicutaneous Priming

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Absence of Foxp3+ Regulatory T Cells during Allergen Provocation Does Not Exacerbate Murine Allergic Airway Inflammation

Cited by 18 publications

References 41 publications

Lung-Infiltrating Foxp3+ Regulatory T Cells Are Quantitatively and Qualitatively Different during Eosinophilic and Neutrophilic Allergic Airway Inflammation but Essential To Control the Inflammation

Lung-Infiltrating Foxp3+ Regulatory T Cells Are Quantitatively and Qualitatively Different during Eosinophilic and Neutrophilic Allergic Airway Inflammation but Essential To Control the Inflammation

CD4+FoxP3+ regulatory T cells suppress fatal T helper 2 cell immunity during pulmonary fungal infection

Superior Suppressive Capacity of Skin Tregs Compared with Lung Tregs in a Model of Epicutaneous Priming

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CD4⁺FoxP3⁺ regulatory T cells suppress fatal T helper 2 cell immunity during pulmonary fungal infection