Dichotomous Role of TGF-β Controls Inducible Regulatory T-cell Fate in Allergic Airway Disease Through Smad3 and TGF-β-activated Kinase 1

Overview

Journal J Allergy Clin Immunol

Specialty Allergy & Immunology

Date 2019 Oct 19

PMID 31626843

Citations 5

Authors

Anthony Joetham

Michaela Schedel

Fangkun Ning

Meiqin Wang

Katsuyuki Takeda

Erwin W Gelfand

Affiliations

Soon will be listed here.

Abstract

Background: Inducible CD4CD25 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-β, which determine the suppressor or enhancing activities of iTreg cells.

Methods: Sensitized wild-type and CD8-deficient (CD8) mice were challenged with allergen. Isolated CD4CD25 T cells were activated by using anti-CD3/anti-CD28. To generate suppressor iTreg cells, cells were then differentiated in the presence of TGF-β, whereas IL-17-producing effector T cells were additionally exposed to IL-6. After TGF-β, Smad3 and TGF-β-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 γt (Rorγt) 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 T17 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 Rorγt and T17 differentiation through histone modifications of Rorγt; Foxp3 expression and iTreg cell-mediated suppression remained intact. In the same cell, TGF-β induced coexpression of Smad3 and TAK1 proteins; in the presence of IL-6, expression of Smad3 and Foxp3 but not TAK1 decreased.

Conclusion: TGF-β 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 T17-mediated autoimmune diseases and neutrophil-dependent asthma.

Citing Articles

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