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J Leukoc Biol. 2019 Aug;106(2):413-430. doi: 10.1002/JLB.2A0618-228R. Epub 2019 Mar 18.

Phosphatase inhibitor PPP1R11 modulates resistance of human T cells toward Treg-mediated suppression of cytokine expression.

Author information

1
Unit of Computational Medicine, Center for Molecular Medicine, Department of Medicine Solna, Karolinska University Hospital and Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
2
Division of Rheumatology, Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
3
Mucosal and Salivary Biology Division, King's College London Dental Institute, London, United Kingdom.
4
Translational Bioinformatics Unit, NavarraBiomed, Departamento de Salud-Universidad Pública de Navarra, Pamplona, Navarra, Spain.
5
Biological and Environmental Sciences and Engineering Division, Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.

Abstract

Regulatory T cells (Tregs) act as indispensable unit for maintaining peripheral immune tolerance mainly by regulating effector T cells. T cells resistant to suppression by Tregs pose therapeutic challenges in the treatment of autoimmune diseases, while augmenting susceptibility to suppression may be desirable for cancer therapy. To understand the cell intrinsic signals in T cells during suppression by Tregs, we have previously performed a global phosphoproteomic characterization. We revealed altered phosphorylation of protein phosphatase 1 regulatory subunit 11 (PPP1R11; Inhibitor-3) in conventional T cells upon suppression by Tregs. Here, we show that silencing of PPP1R11 renders T cells resistant toward Treg-mediated suppression of TCR-induced cytokine expression. Furthermore, whole-transcriptome sequencing revealed that PPP1R11 differentially regulates not only the expression of specific T cell stimulation-induced cytokines but also other molecules and pathways in T cells. We further confirmed the target of PPP1R11, PP1, to augment TCR-induced cytokine expression. In conclusion, we present PPP1R11 as a novel negative regulator of T cell activation-induced cytokine expression. Targeting PPP1R11 may have therapeutic potential to regulate the T cell activation status including modulating the susceptibility of T cells toward Treg-mediated suppression, specifically altering the stimulation-induced T cell cytokine milieu.

KEYWORDS:

CD4 T cell; T cell resistance; immune suppression; immunotherapy; phosphatase; regulatory T cell

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