Phosphoproteomics Reveals Regulatory T Cell-Mediated DEF6 Dephosphorylation That Affects Cytokine Expression in Human Conventional T Cells

Handle URI:
http://hdl.handle.net/10754/625535
Title:
Phosphoproteomics Reveals Regulatory T Cell-Mediated DEF6 Dephosphorylation That Affects Cytokine Expression in Human Conventional T Cells
Authors:
Joshi, Rubin N.; Binai, Nadine A.; Marabita, Francesco; Sui, Zhenhua; Altman, Amnon; Heck, Albert J. R.; Tegner, Jesper ( 0000-0002-9568-5588 ) ; Schmidt, Angelika
Abstract:
Regulatory T cells (Tregs) control key events of immune tolerance, primarily by suppression of effector T cells. We previously revealed that Tregs rapidly suppress T cell receptor (TCR)-induced calcium store depletion in conventional CD4CD25 T cells (Tcons) independently of IP levels, consequently inhibiting NFAT signaling and effector cytokine expression. Here, we study Treg suppression mechanisms through unbiased phosphoproteomics of primary human Tcons upon TCR stimulation and Treg-mediated suppression, respectively. Tregs induced a state of overall decreased phosphorylation as opposed to TCR stimulation. We discovered novel phosphosites (T595_S597) in the DEF6 (SLAT) protein that were phosphorylated upon TCR stimulation and conversely dephosphorylated upon coculture with Tregs. Mutation of these DEF6 phosphosites abrogated interaction of DEF6 with the IP receptor and affected NFAT activation and cytokine transcription in primary Tcons. This novel mechanism and phosphoproteomics data resource may aid in modifying sensitivity of Tcons to Treg-mediated suppression in autoimmune disease or cancer.
KAUST Department:
Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division; Biological and Environmental Sciences and Engineering (BESE) Division
Citation:
Joshi RN, Binai NA, Marabita F, Sui Z, Altman A, et al. (2017) Phosphoproteomics Reveals Regulatory T Cell-Mediated DEF6 Dephosphorylation That Affects Cytokine Expression in Human Conventional T Cells. Frontiers in Immunology 8. Available: http://dx.doi.org/10.3389/fimmu.2017.01163.
Publisher:
Frontiers Media SA
Journal:
Frontiers in Immunology
Issue Date:
25-Sep-2017
DOI:
10.3389/fimmu.2017.01163
Type:
Article
ISSN:
1664-3224
Sponsors:
The proteomics project was supported and performed within the framework of the PRIME-XS project (grant no. 262067) funded by the European Union’s Seventh Framework Programme (FP7). Further support was provided by: Marie-Curie Intra European Fellowship within the European Union’s Seventh Framework Programme (FP7 project ID: 326930; to AS); Dr. Åke Olsson Foundation (to AS); Karolinska Institutet Stiftelser & Fonder (to AS, FM, and JT); CERIC (Center of Excellence for Research on Inflammation and Cardiovascular disease; to AS and JT); European Research Council (FP7, ERC Project ID: 617393; to AS and JT); Torsten Söderberg Foundation (to AS and JT); Roadmap Initiative Proteins@Work (project number 184.032.201; to NB and AH), funded by the Netherlands Organization for Scientific Research (NWO).
Additional Links:
https://www.frontiersin.org/articles/10.3389/fimmu.2017.01163/full
Appears in Collections:
Articles; Biological and Environmental Sciences and Engineering (BESE) Division; Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorJoshi, Rubin N.en
dc.contributor.authorBinai, Nadine A.en
dc.contributor.authorMarabita, Francescoen
dc.contributor.authorSui, Zhenhuaen
dc.contributor.authorAltman, Amnonen
dc.contributor.authorHeck, Albert J. R.en
dc.contributor.authorTegner, Jesperen
dc.contributor.authorSchmidt, Angelikaen
dc.date.accessioned2017-10-02T10:53:16Z-
dc.date.available2017-10-02T10:53:16Z-
dc.date.issued2017-09-25en
dc.identifier.citationJoshi RN, Binai NA, Marabita F, Sui Z, Altman A, et al. (2017) Phosphoproteomics Reveals Regulatory T Cell-Mediated DEF6 Dephosphorylation That Affects Cytokine Expression in Human Conventional T Cells. Frontiers in Immunology 8. Available: http://dx.doi.org/10.3389/fimmu.2017.01163.en
dc.identifier.issn1664-3224en
dc.identifier.doi10.3389/fimmu.2017.01163en
dc.identifier.urihttp://hdl.handle.net/10754/625535-
dc.description.abstractRegulatory T cells (Tregs) control key events of immune tolerance, primarily by suppression of effector T cells. We previously revealed that Tregs rapidly suppress T cell receptor (TCR)-induced calcium store depletion in conventional CD4CD25 T cells (Tcons) independently of IP levels, consequently inhibiting NFAT signaling and effector cytokine expression. Here, we study Treg suppression mechanisms through unbiased phosphoproteomics of primary human Tcons upon TCR stimulation and Treg-mediated suppression, respectively. Tregs induced a state of overall decreased phosphorylation as opposed to TCR stimulation. We discovered novel phosphosites (T595_S597) in the DEF6 (SLAT) protein that were phosphorylated upon TCR stimulation and conversely dephosphorylated upon coculture with Tregs. Mutation of these DEF6 phosphosites abrogated interaction of DEF6 with the IP receptor and affected NFAT activation and cytokine transcription in primary Tcons. This novel mechanism and phosphoproteomics data resource may aid in modifying sensitivity of Tcons to Treg-mediated suppression in autoimmune disease or cancer.en
dc.description.sponsorshipThe proteomics project was supported and performed within the framework of the PRIME-XS project (grant no. 262067) funded by the European Union’s Seventh Framework Programme (FP7). Further support was provided by: Marie-Curie Intra European Fellowship within the European Union’s Seventh Framework Programme (FP7 project ID: 326930; to AS); Dr. Åke Olsson Foundation (to AS); Karolinska Institutet Stiftelser & Fonder (to AS, FM, and JT); CERIC (Center of Excellence for Research on Inflammation and Cardiovascular disease; to AS and JT); European Research Council (FP7, ERC Project ID: 617393; to AS and JT); Torsten Söderberg Foundation (to AS and JT); Roadmap Initiative Proteins@Work (project number 184.032.201; to NB and AH), funded by the Netherlands Organization for Scientific Research (NWO).en
dc.publisherFrontiers Media SAen
dc.relation.urlhttps://www.frontiersin.org/articles/10.3389/fimmu.2017.01163/fullen
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectCD4 T cellen
dc.subjectDEF6en
dc.subjectNFATen
dc.subjectPhosphoproteomicsen
dc.subjectRegulatory T cellen
dc.subjectSLATen
dc.subjectTCR signalingen
dc.subjectTregen
dc.titlePhosphoproteomics Reveals Regulatory T Cell-Mediated DEF6 Dephosphorylation That Affects Cytokine Expression in Human Conventional T Cellsen
dc.typeArticleen
dc.contributor.departmentComputer, Electrical and Mathematical Sciences and Engineering (CEMSE) Divisionen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.identifier.journalFrontiers in Immunologyen
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionUnit of Computational Medicine, Center for Molecular Medicine, Department of Medicine Solna, Karolinska University Hospital, Science for Life Laboratory, Karolinska Institutet, Stockholm, , , Swedenen
dc.contributor.institutionNetherlands Proteomics Centre, Utrecht, , Netherlandsen
dc.contributor.institutionBiomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, , , , Netherlandsen
dc.contributor.institutionNeuroimmunology Unit, Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Stockholm, , , Swedenen
dc.contributor.institutionDivision of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, , United Statesen
kaust.authorTegner, Jesperen
kaust.authorTegner, Jesperen
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