mTORC2 controls Th9 polarization and allergic airway inflammation.

Abstract

BACKGROUND:

T helper type 9 (Th9) cells, a subpopulation of CD4+ T cells, play a critical role in the pathogenesis of allergic airway inflammation. However, it remains unknown whether mTORC2 regulates Th9 differentiation or function during allergic inflammation.

METHODS:

T-cell-specific Rictor-deficient mice, a mouse model of allergic airway inflammation induced by ovalbumin (OVA) sensitization and a mouse model of adoptive transfer of induced Th9 cells, were used to address the roles of mTORC2 in the pathogenesis of allergic airway inflammation. The in vitro Th9 induction, multiple colors flow cytometry, real-time PCR, and Western blots were used to investigate the molecular effects of mTORC2 in Th9 induction.

RESULTS:

The differentiation of naïve CD4+ T cells into Th9 cells was significantly diminished in the absence of Rictor, the core component of mTORC2. Using a mouse model of allergic airway inflammation induced by OVA sensitization, T-cell-specific Rictor-deficient mice show much less severe allergic airway inflammation characterized by decreased pathological alterations and fibrosis of the lungs, which was accompanied with reduced Th9 differentiation and infiltration. Importantly, the isolated Rictor-deficient Th9 cells mediate less severe allergic pathogenesis upon adoptive transfer. Rictor deficiency impairs Th9 cell differentiation by reducing IRF4 expression rather than affecting Foxo1/Foxo3a transcriptional activity, which is likely due to decreased Akt and/or STAT6 activation.

CONCLUSIONS:

These findings uncover a novel role of mTORC2 in Th9 cell differentiation and may have important implications for therapeutic intervention of allergic diseases.

• Authors: H Chen, L Zhang, P Wang, H Su, W Wang, Z Chu, L Zhang, X Zhang, Y Zhao
• Journal: Allergy (Allergy) Vol. 72 Issue 10 Pg. 1510-1520 (Oct 2017) ISSN: 1398-9995 [Electronic] Denmark
• PMID: 28273354 (Publication Type: Journal Article)
• Copyright: © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

Chemical References

• Biomarkers
• Interferon Regulatory Factors
• STAT6 Transcription Factor
• interferon regulatory factor-4
• Mechanistic Target of Rapamycin Complex 2
• Proto-Oncogene Proteins c-akt

Topics

• Adoptive Transfer
• Animals
• Biomarkers
• Cell Differentiation (immunology)
• Disease Models, Animal
• Interferon Regulatory Factors (genetics, metabolism)
• Lymphocyte Activation (immunology)
• Mechanistic Target of Rapamycin Complex 2 (metabolism)
• Mice
• Mice, Knockout
• Proto-Oncogene Proteins c-akt (metabolism)
• Respiratory Hypersensitivity (immunology, metabolism, pathology)
• STAT6 Transcription Factor (metabolism)
• T-Lymphocyte Subsets (immunology, metabolism)
• T-Lymphocytes, Helper-Inducer (cytology, immunology, metabolism)