Phosphatase inhibitor PPP1R11 modulates resistance of human T cells toward Treg-mediated suppression of cytokine expression
AuthorsJoshi, Rubin N.
Fernandes, Sunjay Jude
Shang, Ming Mei
Kiani, Narsis A.
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
Permanent link to this recordhttp://hdl.handle.net/10754/656397
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AbstractRegulatory 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.
CitationJoshi, R. N., Fernandes, S. J., Shang, M., Kiani, N. A., Gomez-Cabrero, D., Tegnér, J., & Schmidt, A. (2019). Phosphatase inhibitor PPP1R11 modulates resistance of human T cells toward Treg-mediated suppression of cytokine expression. Journal of Leukocyte Biology. doi:10.1002/jlb.2a0618-228r
SponsorsR.N.J. performed and analyzed all the T cell experiments. R.N.J. and A.S. designed the project, designed experiments, and interpreted results. R.N.J. wrote the manuscript with contributions from A.S. R.N.J. prepared figures with contributions from A.S. and S.J.F. R.N.J. performed statistical analyses with suggestions from N.A.K. R.N.J., A.S., S.J.F., and D.G.C. designed the RNAseq experiments. R.N.J. and A.S. prepared samples for RNAseq, S.J.F. performed library preparation, quality control, and raw data analysis of RNAseq experiments. S.J.F. and R.N.J. performed downstream analyses of RNAseq data with suggestions from D.G.C. R.N.J. and M.S. performed and analyzed multiplex bead-array immunoassay. J.T. and A.S. supervised research. All the authors approved the final version of the manuscript. The authors thank Peri Noori (Unit of Computational Medicine, Karolinska Institute (KI)) for technical assistance with RNA sequencing. The authors also thank Andrea Introini (Division of Rheumatology, KI) and Natalie Sippl (Department of Medicine, KI) for technical help with multiplex bead-array immunoassay and flow cytometry, respectively. Francesco Marabita (former member of Unit of Computational Medicine, KI) and Nadine A. Binai (formerly Biomolecular Mass Spectrometry and Proteomics, Utrecht University) are credited for their roles in the underlying phosphoproteomic mass-spec study. The authors also acknowledge John Andersson (Immunology and Allergy Unit, KI) and Janne Lehtiö (Department Oncology-Pathology, KI) for useful discussions on the project. This work was supported by grants from Karolinska Institutet Stiftelser & Fonder (2016fobi47574 to A.S.; 2016fobi50265 to J.T.; 2012FoBi34926 to M.S.), Swedish Research Council (Vetenskapsrådet; 2017-04000 to J.T.), and CERIC (Center of Excellence for Research on Inflammation and Cardiovascular disease; to A.S. & J.T.).
JournalJournal of Leukocyte Biology
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