Reciprocal regulation of Th2 and Th17 cells by PAD2-mediated citrullination
Salinger, Ari J.
Holmes, Caitlyn L.
Shelef, Miriam A.
Thompson, Paul R.
UMass Chan AffiliationsThompson Lab
Department of Biochemistry and Molecular Pharmacology
Amino Acids, Peptides, and Proteins
Biochemical Phenomena, Metabolism, and Nutrition
Enzymes and Coenzymes
Immune System Diseases
Immunoprophylaxis and Therapy
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AbstractDysregulated citrullination, a unique form of posttranslational modification catalyzed by the peptidylarginine deiminases (PADs), has been observed in several human diseases, including rheumatoid arthritis. However, the physiological roles of PADs in the immune system are still poorly understood. Here, we report that global inhibition of citrullination enhances the differentiation of type 2 helper T (Th2) cells but attenuates the differentiation of Th17 cells, thereby increasing the susceptibility to allergic airway inflammation. This effect on Th cells is due to inhibition of PAD2 but not PAD4. Mechanistically, PAD2 directly citrullinates GATA3 and RORgammat, 2 key transcription factors determining the fate of differentiating Th cells. Citrullination of R330 of GATA3 weakens its DNA binding ability, whereas citrullination of 4 arginine residues of RORgammat strengthens its DNA binding. Finally, PAD2-deficient mice also display altered Th2/Th17 immune response and heightened sensitivity to allergic airway inflammation. Thus, our data highlight the potential and caveat of PAD2 as a therapeutic target of Th cell-mediated diseases.
JCI Insight. 2019 Nov 14;4(22). pii: 129687. doi: 10.1172/jci.insight.129687. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/41278