Dichotomous role of TGF-β] controls inducible regulatory T-cell fate in allergic airway disease through Smad3 and TGF-β-activated kinase 1

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:145

Article

Joetham, Anthony¹  Schedel, Michaela¹  Ning, Fangkun¹  Wang, Meiqin¹  Takeda, Katsuyuki¹  Gelfand, Erwin W.¹ 

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

关键词: Inducible CD4(+) CD25(+) regulatory T cells;    T(H)17 cells;    epigenetics;    allergic lung;    Smad3;    forkhead box P3;    TGF-beta-activated kinase 1;    retinoic acid-related orphan receptor gamma t;    IL-17;   

DOI  :  10.1016/j.jaci.2019.09.032

来源: Elsevier

【 摘 要 】

Background: Inducible CD4(+) CD25(+) regulatory T (iTreg) cells can become pathogenic effector cells, enhancing lung allergic responses. Objective: We aimed to define the underlying cellular and molecular pathways activated by TGF-beta, which determine the suppressor or enhancing activities of iTreg cells. Methods: Sensitized wild-type and CD8-deficient (CD8(-/-)) mice were challenged with allergen. Isolated CD4(+)CD25(-) T cells were activated by using anti-CD3/anti-CD28. To generate suppressor iTreg cells, cells were then differentiated in the presence of TGF-beta, whereas IL-17-producing effector T cells were additionally exposed to IL-6. After TGF-beta, Smad3 and TGF-beta-activated kinase 1 (TAK1) kinase levels were monitored. The consequences of inhibiting either kinase were determined in vitro and after transfer into CD8(-/-) recipients. Quantitative PCR and chromatin immunoprecipitation were used to monitor gene expression and histone modifications at the retinoic acid-related orphan receptor gamma t (Ror gamma t) locus. Results: In wild-type mice, iTreg cells suppressed lung allergic responses linked to Smad3-dependent forkhead box P3 (Foxp3) expression and IL-10 production. In the presence of IL-6, iTreg cells converted to T(H)17 cells, mediating a neutrophil-dependent enhancement of lung allergic responses in CD8(-/-) mice. Conversion was regulated by TAK1. Inhibition or silencing of TAK1 prevented expression of Ror gamma t and T(H)17 differentiation through histone modifications of Ror gamma t; Foxp3 expression and iTreg cell-mediated suppression remained intact. In the same cell, TGF-beta induced coexpression of Smad3 and TAK1 proteins; in the presence of IL-6, expression of Smad3 and Foxp3 but not TAK1 decreased. Conclusion: TGF-beta regulates iTreg cell outcomes through 2 distinct signal transduction pathways: one Smad3 dependent and the other TAK1 dependent. The balance of these pathways has important implications in T(H)17-mediated autoimmune diseases and neutrophil-dependent asthma.

【 授权许可】

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