title: TGF-β Affects the Differentiation of Human GM-CSF+CD4+T Cells in an Activation- and Sodium-Dependent Manner.
abstract: The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is involved in the pathogenesis of chronic inflammatory diseases such as multiple sclerosis. However, the environmental cues promoting differentiation of GM-CSF producing T cells are unclear. Herein, we performed a broad experimental screening of cytokines and data-driven analysis assessing their ability to induce human GM-CSF+CD4+T cells and their subpopulations. TGF-β was discovered to induce GM-CSF production independently of proliferation and IL-2 signaling including STAT5. In contrast, IL-6 and IL-23 decreased GM-CSF production. On the population level, GM-CSF induction was highly correlated with expression of FOXP3 across cytokine stimulations but not with that of IL-17. However, on single-cell level GM-CSF and IFN-γ expression were most correlated, independently of the cytokine environment. Importantly, under low sodium conditions in the medium or upon stimulation with plate-bound instead of bead-bound anti-CD3 and anti-CD28 antibodies, the effects of TGF-β on GM-CSF, but not on FOXP3, were reversed. Our analysis indicates a novel role for TGF-β in generating GM-CSF+subsets of human CD4+T cells. These results are important for understanding of autoimmune disease and therapeutic considerations.
authors.affiliation: Unit of Computational Medicine, Center for Molecular Medicine, Department of Medicine Solna, Karolinska University Hospital and Science for Life Laboratory, Karolinska Institutet , Stockholm , Sweden.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Éliás
authors.affiliation: Unit of Computational Medicine, Center for Molecular Medicine, Department of Medicine Solna, Karolinska University Hospital and Science for Life Laboratory, Karolinska Institutet , Stockholm , Sweden.
authors.forename: Angelika
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: Unit of Computational Medicine, Center for Molecular Medicine, Department of Medicine Solna, Karolinska University Hospital and Science for Life Laboratory, Karolinska Institutet , Stockholm , Sweden.
authors.forename: Venkateshan
authors.initials: V
authors.lastname: Kannan
authors.affiliation: Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institutet , Stockholm , Sweden.
authors.forename: John
authors.initials: J
authors.lastname: Andersson
authors.affiliation: Unit of Computational Medicine, Center for Molecular Medicine, Department of Medicine Solna, Karolinska University Hospital and Science for Life Laboratory, Karolinska Institutet , Stockholm , Sweden.
authors.forename: Jesper
authors.initials: J
authors.lastname: Tegnér
keywords: GM-CSF; TGF-β; autoimmune diseases; differentiation; human CD4+ T cells; multiple sclerosis; multivariate analysis; sodium