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 datadriven
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.
