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Secretome Screening Reveals Immunomodulating Functions Of www.nature.com/scientificreports OPEN Secretome screening reveals immunomodulating functions of IFNα‑7, PAP and GDF‑7 on regulatory T‑cells Mei Ding1*, Rajneesh Malhotra2, Tomas Ottosson2, Magnus Lundqvist3, Aman Mebrahtu3, Johan Brengdahl1, Ulf Gehrmann2, Elisabeth Bäck4, Douglas Ross‑Thriepland5, Ida Isaksson6, Björn Magnusson1, Kris F. Sachsenmeier7, Hanna Tegel3, Sophia Hober3, Mathias Uhlén3, Lorenz M. Mayr5, Rick Davies5, Johan Rockberg3 & Lovisa Holmberg Schiavone1* Regulatory T cells (Tregs) are the key cells regulating peripheral autoreactive T lymphocytes. Tregs exert their function by suppressing efector 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 diferentiation, proliferation and suppressive function. Identifcation of secreted proteins that afect 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 fow 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 identifed 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 identifed as negative regulators that reduced the expression of both CTLA4 and FOXP3, without afecting cell viability. A transcriptomics analysis supported the diferential efect on Tregs of IFNα‑7 versus other IFNα proteins, indicating diferences in JAK/STAT signaling. A conformational model experiment confrmed 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 identifed 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. Regulatory T cells (Tregs) are key cells in the immune system. Tregs suppress efector T cells by regulating peripheral autoreactive T lymphocytes. Tregs have been shown to play essential roles in the control of a variety of physiological and pathological immune responses including infammatory conditions, autoimmune diseases, and cancer1–3. A number of human autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), have been shown to be caused by disruption of Treg cell function or development of Tregs3–5. 1Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden. 2Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. 3Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology, Stockholm, Sweden. 4Mechanistic Biology and Profling, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden. 5Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK. 6Sample Management, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden. 7Translational Medicine, Oncology R&D, AstraZeneca, Boston, USA. *email: mei.ding@ astrazeneca.com; [email protected] Scientifc Reports | (2021) 11:16767 | https://doi.org/10.1038/s41598-021-96184-z 1 Vol.:(0123456789) www.nature.com/scientificreports/ Tere are two types of Treg cells in vivo: naturally occurring Tregs that are antigen-primed and generated in the thymus, and peripheral/induced Tregs that are diferentiated from naïve conventional T cells (Tconv). Both natural and induced Tregs exert suppressive activity and express the transcription factor forkhead box p3 (FOXP3), recognised as the ‘master regulator’ of Treg cell function 2. Recent studies have shown that peripheral and induced Treg cells are unstable and can lose FOXP3 expression and suppressive function 6. Treg cell func- tion and FOXP3 expression play important roles in autoimmune and infammatory diseases. New modulators regulating FOXP3 expression and its downstream genes will aid the discovery of novel signaling pathways and targets afecting Treg cell function and stability. One downstream gene is cytotoxic T-lymphocyte antigen-4 (CTLA4).Treg cells produce and secrete many proteins including IL-10, TGFβ, IL35, galectin-17–10 to exert the suppressive function on T efector cells. A vast number of receptors including CD3, CD4, CD25, GITR (gluco- corticoid-induced tumour necrosis factor receptor), CD49b, type 1 IFNα receptor5,11–14 have also been shown to be expressed on the cell surface of Treg cells. Numerous studies have demonstrated that secreted factors are involved in regulating Treg cell diferentiation, proliferation and suppressive function. Chen et al. demonstrated that IL2 and TGFβ were essential for diferentiating naïve CD4+ cells to Treg cells 15–17. Several studies showed that IL-10 potentiates Treg diferentiation and maintains FOXP3 expression18, and type-1 interferon negatively regu- lates FOXP3 expression in Treg cells19. Tese results highlight that the secretome, consisting of proteins actively being secreted from cells 20, is of importance for Treg cell function. Tus, screening for efect of the secretome on Treg cells would provide an opportunity to identify relevant protein signals that regulate Treg cell function and stability, and improve our understanding of the role of the secretome in Treg cell function. We have recently developed an assay which measures the stability of the Treg protein markers FOXP3 and CTLA4 in primary human Tregs. We have applied this automated high-throughput assay to identify potent and novel small molecule regulators of the Treg markers and as indicators of the Treg phenotype 21, using a diverse small compound library. Tis resulted in the discovery of intracellular proteins euchromatic histone-lysine N-methyltransferase 2 (EHMT2) and glycogen synthase kinase 3 alpha/beta (GSK3α/β) as positive FOXP3 regulators, and bromodomain and extraterminal domain (BET) as negative regulators of FOXP3 and CTLA4 expression21. In order to identify secreted proteins that regulate FOXP3 and CTLA4 expression, we applied the human Treg fow cytometry phenotypic assay as described21. We screened a library of 575 secreted human proteins that has been generated using a high-throughput approach in mammalian cell-factories22–24. Four proteins including growth and diferentiation factor 7 GDF-7, IL-10, prostatic acid phosphatase PAP and IFNα-7 were identifed as positive regulators that increased FOXP3 and/or CTLA4 protein expression. Ten interferon proteins, were identifed as negative regulators that reduced the expression of both CTLA4 and FOXP3 proteins without afect- ing cell viability. Results Secretome‑based screening. In a secretome-based screen a secretome library, consisting of recombinant produced human proteins, is combined with a disease-relevant cell and readout to identify novel biology and signaling pathways (reviewed in25). Te secretome library is generally produced using high-throughput meth- ods. Proteins that are not feasible to produce will not be included in the library24. Conditioned medium 26 or purifed proteins at varying concentrations22,27 are typically used as screening sample. Production and stratifcation of the secretome library for the Treg screen. Te secretome library was stratifed and produced as described in the method section and as described preciously22. A mammalian expression system was used for expression and a C-terminal afnity tag was used for purifcation. Additional, specifc stratifcation was made for the Treg screen28–31 creating a specifc protein list with a total of 575 proteins included in the screen. Identifcation of secretome protein actives in the human Treg assay by primary screening. Te Treg fow cytometry assay allowed for measurement of multiple parameters, including cell viability, FOXP3 and CTLA4 expression, % FOXP3 + cells, % CTLA4 + cells, simultaneously. We use the gene names FOXP3 and CTLA4 when we refer to gene expression and use “FOXP3/CTLA4 protein expression” when we specifcally refer to expression of the corresponding protein product. 575 proteins (Table S1) were screened in the Treg assay at two concentrations. For most of the proteins, the high concentration was 250 nM and the low concentration was with fve-fold dilution, with PBS included as a neutral control. Te efect of human secretome proteins on Treg stability was measured as efect on FOXP3 and CTLA4 protein expression (illustrated in Fig. 1A). In the primary screen, secretome protein hits were identifed based on ≥ 3 × robust Z-score, or ≤ − 3 × robust Z-score of FOXP3 or CTLA4 expression without negatively afecting cell viability (≥ 85% cell viability required). Te method for calculating robust Z-score is described in the methods
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