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J Autoimmun. 2018 Oct 11. pii: S0896-8411(18)30288-9. doi: 10.1016/j.jaut.2018.09.011. [Epub ahead of print]

Arginine methylation of FOXP3 is crucial for the suppressive function of regulatory T cells.

Author information

1
Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, M5G 2M9, Canada.
2
Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, M5G 2M9, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
3
Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, M5G 2M9, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
4
Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, M5G 2M9, Canada.
5
Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, M5G 2M9, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada. Electronic address: naoto.hirano@uhnresearch.ca.

Abstract

Forkhead box transcription factor 3 (FOXP3) plays a pivotal role in the suppressive function of regulatory T cells. In addition to mRNA levels, FOXP3 activity can also be controlled by posttranslational mechanisms, which have not been studied in a comprehensive manner. Through extensive screening using selective inhibitors, we demonstrate that the inhibition of type I protein arginine methytransferases (PRMTs) attenuates the suppressive functions of regulatory T cells. FOXP3 undergoes methylation on arginine residues at positions 48 and 51 by interacting with protein arginine methyltransferase 1 (PRMT1). The inhibition of arginine methylation confers gene expression profiles representing type I helper T cells to FOXP3+ T cells, which results in attenuated suppressive activity. A methylation-defective mutant of FOXP3 displays less potent activity to suppress xenogeneic graft-versus-host disease in vivo. These results elucidate an important role of arginine methylation to enhance FOXP3 functions and are potentially applicable to modulate regulatory T cell functions.

KEYWORDS:

Arginine methylation; FOXP3; Graft-versus-host disease; PRMT1; Posttranslational modification; Regulatory T cells

PMID:
30318155
DOI:
10.1016/j.jaut.2018.09.011

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