Phosphatase PP2A is essential for T17 differentiation.

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 T17 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 T17 differentiation. These PP2A cKO mice had reduced T17 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 gene transcription. Finally, PP2A inhibitors showed similar effects on T17 cells as were observed in PP2A cKO mice, i.e., decreased T17 differentiation and relative protection of mice from EAE. Taken together, these data demonstrate that phosphatase PP2A is essential for T17 differentiation and that inhibition of PP2A could be a possible therapeutic approach to controlling T17-driven autoimmune diseases.