Inducible and naturally occurring regulatory T cells enhance lung allergic responses through divergent transcriptional pathways

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:139

Article

Joetham, Anthony¹  Schedel, Michaela¹  O'Connor, Brian P.²  Kim, Soohyun¹  Takeda, Katsuyuki¹  Abbott, Jordan¹  Gelfand, Erwin W.¹ 

[1] Natl Jewish Health, Div Cell Biol, Dept Pediat, Denver, CO USA

[2] Natl Jewish Health, Ctr Genes Environm & Hlth, Denver, CO USA

关键词: Inducible and naturally occurring regulatory T cells;    suppression;    enhancement;    asthma;    IL-17;    IL-13;   

DOI  :  10.1016/j.jaci.2016.06.051

来源: Elsevier

【 摘 要 】

Background: Regulatory T cells attenuate development of asthma in wild-type (WT) mice, with both naturally occurring regulatory T (nTreg) cells and inducible regulatory T (iTreg) cells exhibiting suppressive activity. When transferred into CD8-deficient (CD8(-/-)) recipients, both cell types enhanced development of allergen-induced airway hyperresponsiveness. Objective: We sought to determine whether the pathways leading to enhancement of lung allergic responses by transferred nTreg and iTreg cells differed. Methods: nTreg cells (CD4(+)CD25(+)) were isolated from WT mice and iTreg cells were generated from WT CD4(+)CD25(-) T cells after activation in the presence of TGF-beta and transferred into sensitized CD8(-/-) recipients before challenge. Development of airway hyperresponsiveness, cytokine levels, and airway inflammation were monitored. Results: Transfer of nTreg cells enhanced lung allergic responses, as did transfer of iTreg cells. Although anti-IL-13 reduced nTreg cell-mediated enhancement, it was ineffective in iTreg cell-mediated enhancement; conversely, anti-IL-17, but not anti-IL-13, attenuated the enhancement by iTreg cells. Recovered iTreg cells from the lungs of CD8(-/-) recipients were capable of IL-17 production and expressed high levels of signature genes of the T(H)17 pathway, ROR gamma t and Il17, whereas reduced expression of the Treg cell key transcription factor forkhead box p3 (Foxp3) was observed. In vitro exogenous IL-6-induced IL-17 production in iTreg cells, and in vivo conversion of transferred iTreg cells was dependent on recipient IL-6. Conclusions: iTreg cells, similar to nTreg cells, exhibit functional plasticity and can be converted from suppressor cells to pathogenic effector cells, enhancing lung allergic responses, but these effects were mediated through different pathways.

【 授权许可】

Free