New mechanism discovered for TH17 differentiation

The research team headed up by Prof. LU Linrong from the Institute of Immunology publishes an article entitled “Phosphatase PP2A is essential for TH17 differentiation” in the journal of PNAS.

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), LU Linrong et al. discover that the PP2A complex is essential for TH17 differentiation. These PP2A cKO mice have reduced TH17 cell numbers and less severe disease in an experimental autoimmune encephalomyelitis (EAE) model. PP2A deficiency also ablates C-terminal phosphorylation of SMAD2 but increases 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. PP2A inhibitors show similar effects on TH17 cells as are observed in PP2A cKO mice, i.e., and decrease TH17 differentiation and relative protection of mice from EAE.

These findings expand the understanding of the intimate relationship between PP2A overexpression and inflammatory diseases. PP2A, as a Ser/Thr phosphatase, proves to be capable of controlling TH17 differentiation via modulating R-SMADs activity. LU Linrong et al. also demonstrate the translational potential of these findings by showing a therapeutic effect of PP2A inhibitors in controlling autoimmune diseases in the encephalomyelitis model.