Sloan lab publish paper in the Proceedings of the National Academy of Sciences of the United States of America (PNAS)
Working in collaboration with Professor Linrong Lu, Zhejiang University China, this study has arisen directly as a result of the ongoing teaching and research collaboration between the School of Biomedical Sciences, University of Edinburgh and Zhejiang University China. It identifies a key role for the phosphatase PP2A in regulating levels of inflammatory TH17 cells and shows a novel therapeutic strategy to control certain autoimmune diseases may be achieved through small molecule inhibition of PP2A.
Dr Richard Sloan’s lab has published an article in PNAS - “Phosphatase PP2A is essential for TH17 differentiation"
Significance By using a gene knockout that leads to T cell-specific deletion, we reveal the essential role of Ser/Thr phosphatase PP2A in TH17 differentiation. We also show that this works through the regulation of SMAD2/3 phosphorylation status, which elucidates molecular pathways by which PP2A modulates the expression of TH17 phenotypes. This finding extends our understanding of the close relationship between PP2A overexpression and inflammatory disease. PP2A is a Ser/Thr phosphatase shown to be capable of controlling TH17 differentiation via modulating R-SMADs activity. We also demonstrate the translational potential of these findings by showing a therapeutic effect of PP2A inhibitors in controlling autoimmune disease in the encephalomyelitis model. Abstract Phosphatase PP2A expression levels are positively correlated to the clinical severity of systemic lupus erythematosus (SLE) and IL17A cytokine overproduction, indicating a potential role of PP2A in controlling TH17 differentiation and inflammation. By generating a mouse strain with ablation of the catalytic subunit α of PP2A in peripheral mature T cells (PP2A cKO), we demonstrate that the PP2A complex is essential for TH17 differentiation. These PP2A cKO mice had reduced TH17 cell numbers and less severe disease in an experimental autoimmune encephalomyelitis (EAE) model. PP2A deficiency also ablated C-terminal phosphorylation of SMAD2 but increased C-terminal phosphorylation of SMAD3. By regulating the activity of RORγt via binding, the changes in the phosphorylation status of these R-SMADs reduced Il17a gene transcription. Finally, PP2A inhibitors showed similar effects on TH17 cells as were observed in PP2A cKO mice, i.e., decreased TH17 differentiation and relative protection of mice from EAE. Taken together, these data demonstrate that phosphatase PP2A is essential for TH17 differentiation and that inhibition of PP2A could be a possible therapeutic approach to controlling TH17-driven autoimmune diseases.