Reciprocal Regulation of Glycolysis-Driven Th17 Pathogenicity and Regulatory T Cell Stability by Cdc42
| Autor: | Yan Meng, Yuan Li, Fukun Guo, Jun-Qi Yang, Yi Zheng, Khalid W. Kalim |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Autoimmune disease Effector Regulatory T cell Immunology Regulator Peripheral tolerance hemic and immune systems chemical and pharmacologic phenomena macromolecular substances CDC42 Biology medicine.disease Immune tolerance Cell biology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure medicine Immunology and Allergy Glycolysis biological phenomena cell phenomena and immunity 030215 immunology |
| Zdroj: | The Journal of Immunology. 200:2313-2326 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | A balance between Th17 cells and regulatory T cells (Tregs) is important for host immunity and immune tolerance. The underlying molecular mechanisms remain poorly understood. Here we have identified Cdc42 as a central regulator of Th17/Treg balance. Deletion of Cdc42 in T cells enhanced Th17 differentiation but diminished induced Treg differentiation and suppressive function. Treg-specific deletion of Cdc42 decreased natural Tregs but increased effector T cells including Th17 cells. Notably, Cdc42-deficient Th17 cells became pathogenic associated with enhanced glycolysis and Cdc42-deficient Tregs became unstable associated with weakened glycolytic signaling. Inhibition of glycolysis in Cdc42-deficient Th17 cells diminished their pathogenicity and restoration of glycolysis in Cdc42-deficient Tregs rescued their instability. Intriguingly, Cdc42 deficiency in T cells led to exacerbated wasting disease in mouse models of colitis and Treg-specific deletion of Cdc42 caused early, fatal lymphoproliferative diseases. In summary, we show that Cdc42 is a bona fide regulator of peripheral tolerance through suppression of Th17 aberrant differentiation/pathogenicity and promotion of Treg differentiation/stability/function involving metabolic signaling and thus Cdc42 pathway might be harnessed in autoimmune disease therapy. |
| Databáze: | OpenAIRE |
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