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Secretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells.

التفاصيل البيبلوغرافية
العنوان: Secretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells.
المؤلفون: Ding M; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden. mei.ding@astrazeneca.com., Malhotra R; Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Ottosson T; Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Lundqvist M; Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology, Stockholm, Sweden., Mebrahtu A; Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology, Stockholm, Sweden., Brengdahl J; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Gehrmann U; Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Bäck E; Mechanistic Biology and Profiling, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Ross-Thriepland D; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK., Isaksson I; Sample Management, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Magnusson B; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Sachsenmeier KF; Translational Medicine, Oncology R&D, AstraZeneca, Boston, USA., Tegel H; Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology, Stockholm, Sweden., Hober S; Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology, Stockholm, Sweden., Uhlén M; Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology, Stockholm, Sweden., Mayr LM; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK., Davies R; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK., Rockberg J; Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology, Stockholm, Sweden., Schiavone LH; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden. lovisa.holmberg.schiavone@astrazeneca.com.
المصدر: Scientific reports [Sci Rep] 2021 Aug 18; Vol. 11 (1), pp. 16767. Date of Electronic Publication: 2021 Aug 18.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Nature Publishing Group, copyright 2011-
مواضيع طبية MeSH: Bone Morphogenetic Proteins/*immunology , Growth Differentiation Factors/*immunology , Immunologic Factors/*immunology , Interferon-alpha/*immunology , Pancreatitis-Associated Proteins/*immunology , T-Lymphocytes, Regulatory/*immunology, Bone Morphogenetic Proteins/genetics ; Growth Differentiation Factors/genetics ; Humans ; Immunologic Factors/genetics ; Interferon-alpha/genetics ; Pancreatitis-Associated Proteins/genetics
مستخلص: Regulatory T cells (Tregs) are the key cells regulating peripheral autoreactive T lymphocytes. Tregs exert their function by suppressing effector T cells. Tregs have been shown to play essential roles in the control of a variety of physiological and pathological immune responses. However, Tregs are unstable and can lose the expression of FOXP3 and suppressive functions as a consequence of outer stimuli. Available literature suggests that secreted proteins regulate Treg functional states, such as differentiation, proliferation and suppressive function. Identification of secreted proteins that affect Treg cell function are highly interesting for both therapeutic and diagnostic purposes in either hyperactive or immunosuppressed populations. Here, we report a phenotypic screening of a human secretome library in human Treg cells utilising a high throughput flow cytometry technology. Screening a library of 575 secreted proteins allowed us to identify proteins stabilising or destabilising the Treg phenotype as suggested by changes in expression of Treg marker proteins FOXP3 and/or CTLA4. Four proteins including GDF-7, IL-10, PAP and IFNα-7 were identified as positive regulators that increased FOXP3 and/or CTLA4 expression. PAP is a phosphatase. A catalytic-dead version of the protein did not induce an increase in FOXP3 expression. Ten interferon proteins were identified as negative regulators that reduced the expression of both CTLA4 and FOXP3, without affecting cell viability. A transcriptomics analysis supported the differential effect on Tregs of IFNα-7 versus other IFNα proteins, indicating differences in JAK/STAT signaling. A conformational model experiment confirmed a tenfold reduction in IFNAR-mediated ISG transcription for IFNα-7 compared to IFNα-10. This further strengthened the theory of a shift in downstream messaging upon external stimulation. As a summary, we have identified four positive regulators of FOXP3 and/or CTLA4 expression. Further exploration of these Treg modulators and their method of action has the potential to aid the discovery of novel therapies for both autoimmune and infectious diseases as well as for cancer.
(© 2021. The Author(s).)
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المشرفين على المادة: 0 (Bone Morphogenetic Proteins)
0 (GDF7 protein, human)
0 (Growth Differentiation Factors)
0 (IFNA7 protein, human)
0 (Immunologic Factors)
0 (Interferon-alpha)
0 (Pancreatitis-Associated Proteins)
0 (REG3A protein, human)
تواريخ الأحداث: Date Created: 20210819 Date Completed: 20211111 Latest Revision: 20230206
رمز التحديث: 20230206
مُعرف محوري في PubMed: PMC8373891
DOI: 10.1038/s41598-021-96184-z
PMID: 34408239
قاعدة البيانات: MEDLINE
الوصف
تدمد:2045-2322
DOI:10.1038/s41598-021-96184-z