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

Abstract 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, T...

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Autores principales:	Mei Ding, Rajneesh Malhotra, Tomas Ottosson, Magnus Lundqvist, Aman Mebrahtu, Johan Brengdahl, Ulf Gehrmann, Elisabeth Bäck, Douglas Ross-Thriepland, Ida Isaksson, Björn Magnusson, Kris F. Sachsenmeier, Hanna Tegel, Sophia Hober, Mathias Uhlén, Lorenz M. Mayr, Rick Davies, Johan Rockberg, Lovisa Holmberg Schiavone
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3192eee1ef58427faaa5eafd5d5b98ec
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spelling	oai:doaj.org-article:3192eee1ef58427faaa5eafd5d5b98ec2021-12-02T16:45:47ZSecretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells10.1038/s41598-021-96184-z2045-2322https://doaj.org/article/3192eee1ef58427faaa5eafd5d5b98ec2021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-96184-zhttps://doaj.org/toc/2045-2322Abstract 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.Mei DingRajneesh MalhotraTomas OttossonMagnus LundqvistAman MebrahtuJohan BrengdahlUlf GehrmannElisabeth BäckDouglas Ross-ThrieplandIda IsakssonBjörn MagnussonKris F. SachsenmeierHanna TegelSophia HoberMathias UhlénLorenz M. MayrRick DaviesJohan RockbergLovisa Holmberg SchiavoneNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mei Ding Rajneesh Malhotra Tomas Ottosson Magnus Lundqvist Aman Mebrahtu Johan Brengdahl Ulf Gehrmann Elisabeth Bäck Douglas Ross-Thriepland Ida Isaksson Björn Magnusson Kris F. Sachsenmeier Hanna Tegel Sophia Hober Mathias Uhlén Lorenz M. Mayr Rick Davies Johan Rockberg Lovisa Holmberg Schiavone Secretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells
description	Abstract 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.
format	article
author	Mei Ding Rajneesh Malhotra Tomas Ottosson Magnus Lundqvist Aman Mebrahtu Johan Brengdahl Ulf Gehrmann Elisabeth Bäck Douglas Ross-Thriepland Ida Isaksson Björn Magnusson Kris F. Sachsenmeier Hanna Tegel Sophia Hober Mathias Uhlén Lorenz M. Mayr Rick Davies Johan Rockberg Lovisa Holmberg Schiavone
author_facet	Mei Ding Rajneesh Malhotra Tomas Ottosson Magnus Lundqvist Aman Mebrahtu Johan Brengdahl Ulf Gehrmann Elisabeth Bäck Douglas Ross-Thriepland Ida Isaksson Björn Magnusson Kris F. Sachsenmeier Hanna Tegel Sophia Hober Mathias Uhlén Lorenz M. Mayr Rick Davies Johan Rockberg Lovisa Holmberg Schiavone
author_sort	Mei Ding
title	Secretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells
title_short	Secretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells
title_full	Secretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells
title_fullStr	Secretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells
title_full_unstemmed	Secretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells
title_sort	secretome screening reveals immunomodulating functions of ifnα-7, pap and gdf-7 on regulatory t-cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/3192eee1ef58427faaa5eafd5d5b98ec
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Secretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells

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