Coexpression of TGF-β1 and IL-10 Enables Regulatory T Cells to Completely Suppress Airway Hyperreactivity

Abstract

In allergic airway disease, Treg may play an important role in the modulation of airway hyperreactivity (AHR) and inflammation. We therefore investigated the therapeutic potential of Treg in an Ag-dependent murine asthma model. We here describe that AHR can be completely suppressed by adoptive transfer of Treg overexpressing active TGF-β1. Using mice with impaired TGF-β signaling in T cells, we could demonstrate that TGF-β signaling in recipient effector T cells or transferred Treg themselves is not required for the protective effects on AHR. However, the expression of IL-10 by Treg was found to be essential for the suppression of AHR, since Treg overexpressing active TGF-β1 but deficient in IL-10 lacked protective effects. Airway inflammation could not be significantly suppressed by wild-type or transgenic Treg. In conclusion, modulation of cytokine expression by Treg may have therapeutic potential for the treatment of AHR in asthma. The mechanisms of the effects of Treg on airway inflammation require further clarification.

Epistatic interactions between Tgfb1 and genetic loci, Tgfbm2 and Tgfbm3 , determine susceptibility to an asthmatic stimulus

“…In contrast, in a house dust-mite-induced model, anti-TGFβ antibodies had no effect on airway remodeling but exacerbated eosinophilia resulting in potentiated AHR (23). More recently, it was shown that TGFβ produced by bone marrow stromal cells that home to the lung during an asthmatic episode, is implicated in reducing the pulmonary allergic inflammatory response (24), which is consistent with other reports that TGFβ plays a protective role in the asthmatic response (9,10,25,26).…”

Heme Oxygenase-1 Exerts a Protective Role in Ovalbumin-induced Neutrophilic Airway Inflammation by Inhibiting Th17 Cell-mediated Immune Response

“…Tregs are responsible for maintaining immune homeostasis. They can suppress airway inflammation and improve airway remodeling by restraining excessive T-cell immunity, regulating the balance among Th subsets, and decreasing the production of proinflammatory cytokines (49,50). The phosphorylation of STAT5 is considered critical for both Treg development and maintenance as well as Foxp3 expression (29) and is crucial for constraining Th17 cell development (51).…”

Loss of T Regulatory Cell Suppression following Signaling through Glucocorticoid-induced Tumor Necrosis Receptor (GITR) Is Dependent on c-Jun N-terminal Kinase Activation

“…Similar to other reports (6,7), in the absence of CD8-expressing cells, activation of nTregs through GITR in the lungs of recipient mice was shown to be sufficient to abrogate suppression and convert these cells to pathogenic effector cells resulting in the enhancement of lung allergic responses (8). Significantly, GITRL expression in recipients appeared to provide the necessary signals to attenuate suppression, as administration of anti-GITRL antibody prevented rather than enhanced lung allergic responses in association with little increase in levels of IL-13 and maintenance of basal levels of IL-10 and TGF-␤ known to be essential for suppressive activity (12,39).…”