Regulatory T Cells Accumulate in the Lung Allergic Inflammation and Efficiently Suppress T-Cell Proliferation but Not Th2 Cytokine Production

Faustino, Lucas; Mucida, Daniel; Keller, Alexandre C.; Demengeot, Jocelyne; Bortoluci, Karina Ramalho; Sardinha, Luiz Roberto; Takenaka, Maisa C.; Basso, Alexandre Salgado; Faria, Ana Maria Caetano; Russo, Marco

doi:10.1155/2012/721817

Cited by 46 publications

(35 citation statements)

References 61 publications

(91 reference statements)

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“…It was previously reported that anti-CD25 treatment could directly abrogate effector CD25 + T cell responses during an inflammatory episode (28). We have shown that both lung CD25 + and CD25 2 T cells are effector cells because they produce substantial amounts type 2 cytokines (14). In this study, we showed that the vast majority of lunginfiltrating CD4 + T cells were CD25 2 , which are not affected by anti-CD25 treatment.…”

Section: Discussionsupporting

confidence: 51%

“…We have recently shown that Foxp3 + Treg cells accumulate in the lungs of allergic mice and that the majority of these cells upregulated CCR4, CD69, and CD54 and drastically downregulated CD62L, a phenotype that resemble effector/memory T cells, distinguishing from naive CCR4 low CD69 2 CD54 low CD62L high Treg cells (14). Our in vitro studies showed that highly purified infiltrating lung Treg cells efficiently suppress pulmonary Th cell proliferation but fail to inhibit type 2 cytokine production (14).…”

mentioning

confidence: 79%

“…Our in vitro studies showed that highly purified infiltrating lung Treg cells efficiently suppress pulmonary Th cell proliferation but fail to inhibit type 2 cytokine production (14). However, in vivo studies are still necessary to pinpoint and dissect the role of Treg cells in allergic processes or in tolerance.…”

mentioning

confidence: 89%

“…We have previously shown that Treg cells accumulate in the lungs after OVA challenge in allergic mice but not in mice made tolerant by previous OVA feeding (14). To assess the function of Treg cells in vivo, we treated the allergic or tolerant animals with four i.v.…”

Section: Anti-cd25 Treatment Exacerbates Airway Allergic Inflammationmentioning

confidence: 99%

“…We have previously shown that Treg cells accumulated in the lungs of allergic mice were phenotypically different from those present in lymphoid organs and could be characterized among other activation markers as CCR4 + (14). Therefore, we first monitored the appearance of Treg cells in the lungs of allergic or tolerant mice.…”

Section: Foxp3mentioning

confidence: 99%

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Regulatory T Cells Migrate to Airways via CCR4 and Attenuate the Severity of Airway Allergic Inflammation

Faustino

Fonseca

Takenaka

et al. 2013

The Journal of Immunology

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We have previously shown that regulatory T (Treg) cells that accumulate in the airways of allergic mice upregulate CC-chemokine receptor 4 (CCR4) expression. These Treg cells suppressed in vitro Th2 cell proliferation but not type 2 cytokine production. In the current study, using a well-established murine model of allergic lung disease or oral tolerance, we evaluated the in vivo activity of Treg cells in allergic airway inflammation with special focus on CCR4 function. We found that allergic, but not tolerant, mice treated with anti-CD25 Ab showed increased airway eosinophilia and IL-5– or IL-4–producing Th2 cells when compared with untreated mice. Notably, mice with CCR4 deficiency displayed an augmented airway allergic inflammation compared with wild-type or CCR2 knockout (KO) mice. The allergic phenotype of CCR4KO mice was similar to that observed in anti-CD25–treated mice. The exacerbated allergic inflammation of CCR4KO mice was directly associated with an impaired migration of Treg cells to airways and augmented frequency of pulmonary Th2 cells. Adoptive transfer of CD25+CD4+ T cells expressing high levels of CCR4, but not CCR4KO CD25+CD4+ T cells, attenuated the severe airway Th2 response of CCR4KO mice. Our results show that CCR4 is critically involved in the migration of Treg cells to allergic lungs that, in turn, attenuate airway Th2 activation and allergic eosinophilic inflammation.

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Section: Discussionsupporting

confidence: 51%

mentioning

confidence: 79%

mentioning

confidence: 89%

Section: Anti-cd25 Treatment Exacerbates Airway Allergic Inflammationmentioning

confidence: 99%

Section: Foxp3mentioning

confidence: 99%

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Regulatory T Cells Migrate to Airways via CCR4 and Attenuate the Severity of Airway Allergic Inflammation

Faustino

Fonseca

Takenaka

et al. 2013

The Journal of Immunology

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IL-4/CCL22/CCR4 Axis Controls Regulatory T-Cell Migration That Suppresses Inflammatory Bone Loss in Murine Experimental Periodontitis

Araujo-Pires¹,

Vieira²,

Francisconi³

et al. 2014

Journal of Bone and Mineral Research

104

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Inflammatory bone resorption is a hallmark of periodontitis, and Tregs and Th2 cells are independently associated with disease progression attenuation. In this study, we employed an infection-triggered inflammatory osteolysis model to investigate the mechanisms underlying Treg and Th2 cell migration and the impact on disease outcome. Aggregatibacter actinomycetemcomitans–infected C57Bl/6 (wild-type [WT]) mice develop an intense inflammatory reaction and alveolar bone resorption, and Treg and Th2 cell migration is temporally associated with disease progression attenuation. Tregs extracted from the lesions preferentially express CCR4 and CCR8, whereas Th2 cells express CCR3, CCR4, and CCR8. The absence of CCR5 and CCR8 did not significantly impact the migration of Tregs and Th2 cells or affect the disease outcome. CCR4KO mice presented a minor reduction in Th2 cells in parallel with major impairment of Treg migration, which was associated with increased inflammatory bone loss and higher proinflammatory and osteoclastogenic cytokine levels. The blockade of the CCR4 ligand CCL22 in WT mice resulted in an increased inflammatory bone loss phenotype similar to that in the CCR4KO strain. Adoptive transfer of CCR4+ Tregs to the CCR4KO strain revert the increased disease phenotype to WT mice–like levels; also, the in situ production of CCL22 in the lesions is mandatory for Tregs migration and the consequent bone loss arrest. The local release of exogenous CCL22 provided by poly(lactic-co-glycolic acid) (PLGA) microparticles promotes migration of Tregs and disease arrest in the absence of endogenous CCL22 in the IL-4KO strain, characterized by the lack of endogenous CCL22 production, defective migration of Tregs, and exacerbated bone loss. In summary, our results show that the IL-4/CCL22/CCR4 axis is involved in the migration of Tregs to osteolytic lesion sites, and attenuates development of lesions by inhibiting inflammatory migration and the production of proinflammatory and osteoclastogenic mediators.

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TLR9 agonist adsorbed to alum adjuvant prevents asthma-like responses induced by Blomia tropicalis mite extract

Nunes¹,

Alberca²,

Gomes³

et al. 2019

Journal of Leukocyte Biology

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Blomia tropicalis mite is highly prevalent in tropical and subtropical regions and it is associated with allergic diseases such as rhinitis and asthma. By using an OVA‐model of allergic lung disease, we have previously shown that sensitization in the presence of toll like receptors (TLRs) agonists attenuates subsequent OVA‐induced allergic responses. Here, we evaluated the effect of CpG‐ODN, a specific synthetic TLR‐9 agonist, on the development of experimental asthma induced by Blomia tropicalis extract, a relevant source of aeroallergens. Among different protocols of Blomia tropicalis extract sensitization, the subcutaneous sensitization in the presence of alum adjuvant induced the highest Th2 responses, including high IgE levels. Adsorption of CpG to Blomia tropicalis extract/Alum attenuated the airway hyperreactivity, the infiltration of inflammatory cells including eosinophils, and the IL‐5 content in BAL. In addition, lung peribronchial inflammatory infiltrate, mucus production and IL‐5‐producing CD3+CD4+ T cells were significantly reduced in the Blomia tropicalis extract/Alum+CpG group. Importantly, CpG inhibited total IgE production as well as active systemic or cutaneous anaphylaxis reactions. Inhibition of pulmonary Th2 responses was associated with increased IL‐10 production but not with IFN‐γ production. Notably, in IL‐10‐deficient mice, sensitization with OVA/Alum+CpG resulted in intense lung neutrophilia and IFN‐γ production, indicating that IL‐10 is necessary to inhibit subsequent Th1 immunity. Our work highlights the mechanisms of allergy attenuation by CpG and it indicates the potential use of Alum‐based formulation with CpG to treat allergic processes.

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Regulatory T Cells Accumulate in the Lung Allergic Inflammation and Efficiently Suppress T-Cell Proliferation but Not Th2 Cytokine Production

Cited by 46 publications

References 61 publications

Regulatory T Cells Migrate to Airways via CCR4 and Attenuate the Severity of Airway Allergic Inflammation

Regulatory T Cells Migrate to Airways via CCR4 and Attenuate the Severity of Airway Allergic Inflammation

IL-4/CCL22/CCR4 Axis Controls Regulatory T-Cell Migration That Suppresses Inflammatory Bone Loss in Murine Experimental Periodontitis

TLR9 agonist adsorbed to alum adjuvant prevents asthma-like responses induced by Blomia tropicalis mite extract

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