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Coronavirus disease 2019 (COVID‐19) is caused by SARS‐CoV‐2, a novel coronavirus strain. Some studies suggest that COVID‐19 could be an immune‐related disease, and failure of effective immune responses in initial stages of viral infection could contribute to systemic inflammation and tissue damage, leading to worse disease outcomes. T cells can act as a double‐edge sword with both pro‐ and anti‐roles in the progression of COVID‐19. Thus, better understanding of their roles in immune responses to SARS‐CoV‐2 infection is crucial. T cells primarily react to the spike protein on the coronavirus to initiate antiviral immunity; however, T‐cell responses can be suboptimal, impaired or excessive in severe COVID‐19 patients. This review focuses on the multifaceted roles of T cells in COVID‐19 pathogenesis and rationalizes their significance in eliciting appropriate antiviral immune responses in COVID‐19 patients and unexposed individuals. In addition, we summarize the potential therapeutic approaches related to T cells to treat COVID‐19 patients. These include adoptive T‐cell therapies, vaccines activating T‐cell responses, recombinant cytokines, Th1 activators and Th17 blockers, and potential utilization of immune checkpoint inhibitors alone or in combination with anti‐inflammatory drugs to improve antiviral T‐cell responses against SARS‐CoV‐2., This review focuses on the multi‐faceted roles of T cells in COVID‐19 pathogenesis and rationalizes their significance in eliciting appropriate antiviral immune responses in COVID‐19 patients and unexposed individuals. In addition, wesummarize the potential therapeutic approaches related to T cells to treat COVID‐19 patients.

Despite recent advances in colorectal cancer (CRC) treatment, a large proportion of patients show limited responses to therapies, especially in advanced stages. There is an urgent need to identify prognostic biomarkers and/or therapeutic targets in advanced stages, aiming to improve the efficacy of current treatments. We aimed to determine prognostic biomarkers in tumor tissue and circulation of CRC patients, with a special focus on T cell exhaustion markers. We found that mRNA levels of PD-1, TIM-3, CTLA-4, TIGIT, CD160, CD244, KLRG1, TOX2, TOX3, Ki-67, and PRDM1 were elevated in CRC tumor tissues. We also investigated differences in gene expression between early and advanced disease stages. We found that TOX and potentially TIM-3, CTLA-4, VISTA, TIGIT, KLRG1, TOX2, SIRT1, Ki-67, and Helios mRNA levels in tumor tissue were elevated in advanced disease stages, suggesting their potential roles in CRC progression. In contrast, PD-1 and CD160 levels in tumor tissue were downregulated in advanced stages. In the circulation of CRC patients, mRNA levels of PD-1, VISTA and LAG-3 were higher than those of healthy individuals. Moreover, in circulation, PD-1, CTLA-4 and TIGIT mRNA levels were reduced in advanced stages. Interestingly, levels of PD-1 in both tumor tissue and circulation were reduced in advanced stages, suggesting that targeting PD-1 in patients with advanced stages could be less effective. Altogether, these findings suggest some potential T cell exhaustion markers that could be utilized as prognostic biomarkers and/or therapeutic targets for CRC. However, further investigations and validations in larger cohorts are required to confirm these findings.Other Information Published in: Cancer Immunology, Immunotherapy License: https://creativecommons.org/licenses/by/4.0See article on publisher's website: http://dx.doi.org/10.1007/s00262-020-02593-w

Myeloid cells, including antigen-presenting cells (APCs) and myeloid-derived suppressor cells (MDSCs) play opposing roles to orchestrate innate and adaptive immune responses during physiological and pathological conditions. We investigated the role of DNA methylation in regulating the transcription of inhibitory/suppressive molecules in myeloid suppressive cells (identified as CD33+HLA-DR–) in comparison to APCs. We selected a number of immune checkpoints (ICs), IC ligands, and immunosuppressive molecules that have been implicated in MDSC function, including PD-L1, TIM-3, VISTA, galectin-9, TGF-β, ARG1 and MMP9. We examined their mRNA expression levels, and investigated whether DNA methylation regulates their transcription in sorted myeloid cell subpopulations. We found that mRNA levels of PD-L1, TIM-3, TGF-β, ARG1 and MMP9 in CD33+HLA-DR– cells were higher than APCs. However, VISTA and galectin-9 mRNA levels were relatively similar in both myeloid subpopulations. CpG islands in the promoter regions of TGF-β1, TIM-3 and ARG1 were highly unmethylated in CD33+HLA-DR–cells, compared with APCs, suggesting that DNA methylation is one of the key mechanisms, which regulate their expression. However, we did not find differences in the methylation status of PD-L1 and MMP9 between CD33+HLA-DR– and APCs, suggesting that their transcription could be regulated via other genetic and epigenetic mechanisms. The promoter methylation status of VISTA was relatively similar in both myeloid subpopulations. This study provides novel insights into the epigenetic mechanisms, which control the expression of inhibitory/suppressive molecules in circulating CD33+HLA-DR– cells in a steady-state condition, possibly to maintain immune tolerance and haemostasis.

Additional file 1: Figure S1. Adherent junction pathway in tumor-infiltrating PMN-MDSCs. The upregulated genes in PMN-MDSCs from 2 patients were uploaded in DAVID to identify the biological pathways. Adherent junction is the top KEGG pathway regulated in PMN-MDSCs, compared with APCs within the TME. The black ovals highlight the KEGG identified functional pathways that are regulated by PMN-MDSCs, within the TME. The functional consequences of related genes are shown in red. Figure S2. HIF-1 signaling pathway in tumor-infiltrating I-MDSCs. The downregulated genes in PMN-MDSCs, compared with I-MDSCs from two patients were uploaded in DAVID to identify the biological pathways. HIF-1 signaling is the top KEGG pathway regulated in I-MDSCs, within the TME. The black ovals highlight the KEGG identified functional pathways that are regulated by I-MDSCs, within the TME. The functional consequences of related genes are shown in red. Figure S3. Validation of differential gene expression and functional network analyses of APCs, PMN-MDSCs and I-MDSCs in CRC patients. Heat maps show the TPM representing fold change to the mean expression of WNT signaling, SNARE signaling and JNK pathway activation in I-MDSCs (A). Heat maps show the TPM representing fold change relative to the mean expression of colorectal cancer-, cell migration-, NFκB-, IL-1β production-related genes in PMN-MDSCs, compared with APCs (B). Heat map shows the TPM representing fold change relative to the mean expression of tumor progression-, migration and metastasis- and DNA methylation-related genes in PMN-MDSCs (C). Results obtained from four CRC patients (#09, #12, #13, and #16). Figure S4. CD11a expression in tumor-infiltrating PMN-MDSCs. Heat map shows the TPM representing fold change relative to the mean expression of CD11a gene (ITGAL) in PMN-MDSCs (A). Cells isolated from TT of #07 and #08 patients were stained for myeloid cell markers and CD11a, and analyzed by flow cytometry. Representative flow cytometric plots show the gating strategy employed to identify I-MDSCs and PMN-MDSCs expressing CD11a (B).

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells with potent immunosuppressive functions, which can inhibit the activation of immune responses under a steady-state condition and pathological conditions. We performed transcriptomic profiling of circulating CD33+HLA-DR+ myeloid antigen-presenting cells (APCs) and CD33+HLA-DR– myeloid cells (potentially MDSCs) in healthy individuals. We sorted both subpopulations from peripheral blood mononuclear cells (PBMCs) of 10 healthy donors and performed RNA sequencing (RNA-Seq). We found that several signaling pathways associated with the positive regulation of immune responses, such as antigen presentation/processing, FcγR-mediated phagocytosis and immune cell trafficking, phosphoinositide 3-kinase (PI3K)/Akt signaling, DC maturation, triggering receptor expressed on myeloid cells 1 (TREM1) signaling, nuclear factor of activated T cells (NFAT) and IL-8 signaling were downregulated in CD33+HLA-DR– myeloid cells. In contrast, pathways implicated in tumor suppression and anti-inflammation, including peroxisome proliferator-activated receptor (PPAR) and phosphatase and tensin homolog (PTEN), were upregulated in CD33+HLA-DR– myeloid cells. These data indicate that PPAR/PTEN axis could be upregulated in myeloid cells to keep the immune system in check in normal physiological conditions. Our data reveal some of the molecular and functional differences between CD33+HLA-DR+ APCs and CD33+HLA-DR– myeloid cells in a steady-state condition, reflecting the potential suppressive function of CD33+HLA-DR– myeloid cells to maintain immune tolerance. For future studies, the same methodological approach could be applied to perform transcriptomic profiling of myeloid subsets in pathological conditions.

Due to Industry 4.0 (I4.0) the software ecosystem is constantly changing, and new possibilities and challenges are arising. The purpose of this Master Thesis is to map the software ecosystem in the automotive industry in order to understand the position of Atlas Copco and what gaps an industrial tool supplier can close. In addition, find out what opportunities and challenges that exist in the ecosystem today. Since Industry 4.0 and the software ecosystem are relatively new topics and alters continuously, the study was carried out in an abductive approach and a research design model was created according to that. By combining literature study with empirical study such as interviews, a better understanding was gained which laid the foundation of accumulating a deeper knowledge about the research field and made it feasible to answer the research questions. The current structure in different markets of the software ecosystem are shaped according to an old industry standard for modelling system structures. Differences and similarities between the markets can be found, which explains difficulties in providing software globally. By analysing and combining the current structures for each market, including the answers gained from the conducted interviews, a model was created. A new model for the definition of a software ecosystem in the automotive industry was the result. Additionally, a new way of structuring and visualizing the generic structure of the software ecosystem for Atlas Copco in the Automotive industry was presented as well. The latter model could be used as a tool, that enables a better understanding of the software ecosystem as well as a way to present new solutions to customers. In the ecosystem Atlas Copco takes the role as a premium industrial tool supplier and a provider of software used to configure and monitor quality and errors in the assembly processes. Hence, they broaden their market to become a software supplier. However, thanks to I4.0 technologies, there are potential areas in the production where it is possible for Atlas Copco to extend their establishment further to get more market shares of the software market as well as to provide more value to their customers. Although, the recommendation for Atlas Copco is to shape a reference architecture and focus on software close to the operations of industrial equipment. Mjukvaruekosystemet är något som ständigt är i förändring där nya möjligheter och utmaningar uppstår i ekosystemet i anknytning till Industri 4.0 (I4.0). Syftet med denna masteruppsats är att kartlägga mjukvaruekosystemet i fordonstillverkningsindustrin för ta reda på vilken position AtlasCopco har och vilka luckor en industriverktygsleverantör kan sluta samt undersöka utmaningar och möjligheter som existerar idag. En forskningsdesignmodell skapades och eftersom projektet omfattar ämnet Industri 4.0 samt mjukvaruekosystemet som är ett relativt nytt ämne som är under kontinuerlig förändring, så utfördes studien baserat på abduktiv strategi. Genom att kombinera litteraturstudier med empiriska studier som intervjuer erhölls en bättre förståelse som lade grunden för att vidare samla på djupare kunskap om forskningsområdet vilket gjorde det möjligt att svara på forskningsfrågorna. Den nuvarande strukturen på olika marknader i mjukvaruekosystemet formas enligt en gammal branschstandard för ett modelleringssystemstrukturer. Skillnader och likheter mellan marknaderna har presenterats som förklarar svårigheterna med att tillhandahålla programvara globalt. I samband med att analysera och kombinera de nuvarande strukturerna för varje marknad, inklusive svaren från de genomförda intervjuerna, har modeller tagits fram. I resultatet presenteras en ny modell för att definiera ett mjukvaruekosystem inom bilindustrin. Dessutom presenterades också ett nytt sätt att strukturera och visualisera den generiska strukturen i mjukvaruekosystemet för Atlas Copco inom fordonsindustrin. Modellen kan användas som ett verktyg för att lättare förstå mjukvaruekosystemet, och till att presentera nya lösningar för kunderna. I ekosystemet tar AtlasCopco rollen som en premiumleverantör av industriella verktyg, inklusive att tillhandahålla programvara som används för att konfigurera, övervaka kvalitet och fel i monteringsprocesserna. Detta breddar Atlas Copcos marknad till att även bli en mjukvaruleverantör. Tack vare I4.0 teknik finns det potentiella produktionsområden där det är möjligt för Atlas Copco att etablera sig ännu mer, för att få fler marknadsandelar på mjukvarumarknaden samt ge mer värde till sina kunder. Rekommendationen är att Atlas Copco skapar en referensarkitektur samt fokusera på mjukvara nära kopplat till operationsnivån och industriverktyg.