CD8+ T Cell-Mediated Airway Hyperresponsiveness and Inflammation Is Dependent on CD4+IL-4+ T Cells

Koya, Toshiyuki; Miyahara, Nobuaki; Takeda, Katsuyuki; Matsubara, Shigeki; Matsuda, Hiroyuki; Swasey, Christina H.; Balhorn, Annette; Dakhama, Azzeddine; Gelfand, Erwin W.

doi:10.4049/jimmunol.179.5.2787

Cited by 48 publications

(50 citation statements)

References 58 publications

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“…We and others also found that numbers of CD8 + IL-13 + cells were increased in experimental asthma models in mice (8)(9)(10) as a result of their activation by IL-4-producing CD4 + T cells (11). CD8 + T cells can be polarized to effector subsets with cytokine profiles similar to those found in CD4 + T cells (12)(13)(14).…”

Section: Il-13supporting

confidence: 53%

Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8⁺T cell skewing in allergic lung disease

Jia

Domenico

Takeda

et al. 2013

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

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Allergic asthma is a heterogeneous inflammatory disorder of the airways characterized by chronic airway inflammation and airway hyperresponsiveness. Numbers of CD8 + IL-13 + T cells are increased in asthmatics and during the development of experimental asthma in mice. In an atopic environment rich in IL-4, these CD8 + T cells mediate asthmatic responses, but the mechanisms regulating the conversion of CD8 + effector T cells from IFN-γ– to pathogenic IL-13–producing effector cells that contribute to an asthma phenotype have not been defined. Here, we show that cholesterol side-chain cleavage P450 enzyme, Cyp11a1, is a key regulator of CD8 + T-cell conversion. Expression of the gene, protein, and enzymatic activity of Cyp11a1 were markedly increased in CD8 + T cells differentiated in the presence of IL-2 plus IL-4 compared with cells differentiated in IL-2 alone. Inhibition of Cyp11a1 enzymatic activity with aminoglutethimide or reduction in the expression of Cyp11a1 using short hairpin RNA prevented the IL-4–induced conversion of IFN-γ– to IL-13–producing cells without affecting expression of the lineage-specific transcription factors T-box expressed in T cells (T-bet) or GATA binding protein 3 (GATA3). Adoptive transfer of aminoglutethimide-treated CD8 + T cells into sensitized and challenged CD8-deficient recipients failed to restore airway hyperresponsiveness and inflammation. We demonstrate that Cyp11a1 controls the phenotypic conversion of CD8 + T cells from IFN-γ to IL-13 production, linking steroidogenesis in CD8 + T cells, a nonclassical steroidogenic tissue, to a proallergic differentiation pathway.

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Section: Il-13supporting

confidence: 53%

Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8⁺T cell skewing in allergic lung disease

Jia

Domenico

Takeda

et al. 2013

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

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“…This BMDC transfer model was shown to induce AHR and airway eosinophilia, but to a less robust extent than in models where mice were systemically sensitized and then challenged via the airways (19). Nonetheless, these responses following BMDC transfer were shown to be dependent on both IL-4-producing CD4…”

Section: Discussionmentioning

confidence: 98%

“…ϩ T cells and APCs pulsed with Ag (19). To first determine the consequences of inhibiting Notch signaling in CD4 ϩ T cells on the development of lung allergic responses, we used the BMDC transfer model in which the transfer of allergen-pulsed BMDCs intratracheally before allergen challenge was shown to be essential (44).…”

Section: Discussionmentioning

confidence: 99%

Jagged1 on Dendritic Cells and Notch on CD4+ T Cells Initiate Lung Allergic Responsiveness by Inducing IL-4 Production

Okamoto

Matsuda

Joetham

et al. 2009

The Journal of Immunology

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Jagged1, a Notch ligand, and Notch have been implicated in Th2 differentiation, but their role in initiating IL-4 production and Th2 differentiation in vivo and the development of allergic airway responses has not been defined. In this study, we show that Jagged1 is up-regulated on bone marrow-derived dendritic cells (BMDCs) pulsed with allergen and that the transfer of these BMDCs before allergen challenge induces airway hyperresponsiveness (AHR) and eosinophilic airway inflammation. Treatment of CD4+ T cells with a γ-secretase inhibitor (GSI), which inhibits Notch signaling, resulted in decreased cytokine production when the cells were cocultured with allergen-pulsed, Jagged1-expressing BMDCs and, after the transfer of allergen-pulsed BMDCs, IL-4-deficient (IL-4−/−) recipients of GSI-treated naive CD4+ T cells developed lower levels of AHR, reduced numbers of eosinophils, and lower Th2 cytokine levels when challenged with allergen. In vivo treatment of wild-type mice with Jagged1-Fc enhanced AHR and airway inflammation, whereas the transfer of BMDC transfected with Jagged1 small interfering RNA (siRNA) cells into WT or IL-4−/− mice before transfer of CD4+ T cells resulted in decreased AHR, inflammation, and Th2 cytokines, indicating the critical role for Jagged1 expression on APCs. These data identify the essential role of the interactions between Notch on CD4+ T cells and Jagged1 on APCs in the initiation of IL-4 production and Th2 differentiation for the development of AHR and allergic airway inflammation.

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“…CD4 + T cells, particularly Th2 cells, play a pivotal role in allergic airway inflammation. Interactions between CD4 + and CD8 + T cells, in part through IL-4 during the sensitization phase, are essential to the development of CD8 + IL-13 + T cell-dependent airway allergic inflammation [33] . The present study demonstrates that in normal E3 rats, there is no significant difference in the potency and efficacy of relaxation induced by isoprenaline, an agonist of β 2 -adrenoceptor in airways.…”

Section: Discussionmentioning

confidence: 99%

Alteration of airway responsiveness mediated by receptors in ovalbumin-induced asthmatic E3 rats

Yang

Cao

et al. 2009

Acta Pharmacol Sin

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Aim: Airway hyperresponsiveness is a constant feature of asthma. The aim of the present study was to investigate airway hyperreactivity mediated by contractile and dilative receptors in an ovalbumin (OVA)-induced model of rat asthma. Methods: Asthmatic E3 rats were prepared by intraperitoneal injection with OVA/aluminum hydroxide and then challenged with intranasal instillation of OVA-PBS two weeks later. The myograph method was used to measure the responses of constriction and dilatation in the trachea, main bronchi and lobar bronchi. Results: In asthmatic E3 rats, β 2 adrenoceptor-mediated relaxation of airway smooth muscle pre-contracted with 5-HT was inhibited, and there were no obvious difference in relaxation compared with normal E3 rats. Contraction of lobar bronchi mediated by 5-HT and sarafotoxin 6c was more potent than in the trachea or main bronchi. Airway contractions mediated by the endothelin (ET) A receptor, ET B receptor and M 3 muscarinic receptor were augmented, and the augmented contraction was most obvious in lobar bronchi. The order of efficacy of contraction for lobar bronchi induced by agonists was ET-1, sarafotoxin 6c>ACh>5-HT. OX8 (an antibody against CD8 + T cells) strongly shifted and OX35 (an antibody against CD4 + T cells) modestly shifted isoprenaline-induced concentration-relaxation curves in a nonparallel fashion to the left with an increased R max in asthmatic rats and sarafotoxin 6c-induced concentration-contractile curves to the right with a decreased E max . Conclusion: The inhibition of airway relaxation and the augmentation of contraction mediated by receptors contribute to airway hyperresponsiveness and involve CD8 + and CD4 + T cells.

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CD8+ T Cell-Mediated Airway Hyperresponsiveness and Inflammation Is Dependent on CD4+IL-4+ T Cells

Cited by 48 publications

References 58 publications

Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8⁺T cell skewing in allergic lung disease

Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8⁺T cell skewing in allergic lung disease

Jagged1 on Dendritic Cells and Notch on CD4+ T Cells Initiate Lung Allergic Responsiveness by Inducing IL-4 Production

Alteration of airway responsiveness mediated by receptors in ovalbumin-induced asthmatic E3 rats

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CD8+ T Cell-Mediated Airway Hyperresponsiveness and Inflammation Is Dependent on CD4+IL-4+ T Cells

Cited by 48 publications

References 58 publications

Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8+T cell skewing in allergic lung disease

Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8+T cell skewing in allergic lung disease

Jagged1 on Dendritic Cells and Notch on CD4+ T Cells Initiate Lung Allergic Responsiveness by Inducing IL-4 Production

Alteration of airway responsiveness mediated by receptors in ovalbumin-induced asthmatic E3 rats

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Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8⁺T cell skewing in allergic lung disease

Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8⁺T cell skewing in allergic lung disease