Phosphoproteomics Reveals Regulatory T Cell-Mediated DEF6 Dephosphorylation That Affects Cytokine Expression in Human Conventional T Cells
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Type
ArticleAuthors
Joshi, Rubin N.Binai, Nadine A.
Marabita, Francesco
Sui, Zhenhua
Altman, Amnon
Heck, Albert J. R.
Tegner, Jesper

Schmidt, Angelika

KAUST Department
Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) DivisionBiological and Environmental Sciences and Engineering (BESE) Division
Date
2017-09-25Permanent link to this record
http://hdl.handle.net/10754/625535
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Show full item recordAbstract
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.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.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).Publisher
Frontiers Media SAJournal
Frontiers in ImmunologyISSN
1664-3224PubMed ID
28993769Additional Links
https://www.frontiersin.org/articles/10.3389/fimmu.2017.01163/fullae974a485f413a2113503eed53cd6c53
10.3389/fimmu.2017.01163
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