Reciprocal regulation of Th2 and Th17 cells by PAD2-mediated citrullination

Abstract Dysregulated citrullination, a unique form of post-translational modification catalyzed by the peptidylarginine deiminases (PADs), is associated with several major risk factors of rheumatoid arthritis, a disease characterized by the presence of anti-citrullinated protein antibodies. While PADs have been identified decades ago, their physiological roles in the immune system are still poorly understood. Hereby we report that PAD2 is the dominant PAD in Th cells. Its expression is induced by anti-CD3 stimulation. Pharmacological inhibition or genetic ablation of PAD2 augments Th2 differentiation but attenuates Th17 differentiation of human and mouse primary Th cells. This effect is due to alterations in the activity of GATA3 and RORgt. Mechanistically, both GATA3 and RORgt interact with and are citrullinated by PAD2 in primary Th cells. Citrullination of R330 of GATA3 weakens its DNA binding ability, whereas citrullination of four arginine residues of RORgt enhances its DNA binding. Furthermore, PAD2-deficient mice are more susceptible to allergic airway inflammation. Taken together, PAD2-mediated citrullination reciprocally regulates the differentiation of Th2 and Th17 cells.