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Journal Articles Proceedings of the National Academy of Sciences of the United States of America Year : 2021

CD4 + T cells require Ikaros to inhibit their differentiation towards a pathogenic cell fate

Abstract

The production of proinflammatory cytokines, particularly granulocyte-macrophage colony-stimulating factor (GM-CSF), by pathogenic CD4+ T cells is central for mediating tissue injury in inflammatory and autoimmune diseases. However, the factors regulating the T cell pathogenic gene expression program remain unclear. Here, we investigated how the Ikaros transcription factor regulates the global gene expression and chromatin accessibility changes in murine T cells during Th17 polarization and after activation via the T cell receptor (TCR) and CD28. We found that, in both conditions, Ikaros represses the expression of genes from the pathogenic signature, particularly Csf2, which encodes GM-CSF. We show that, in TCR/CD28-activated T cells, Ikaros binds a critical enhancer downstream of Csf2 and is required to regulate chromatin accessibility at multiple regions across this locus. Genome-wide Ikaros binding is associated with more compact chromatin, notably at multiple sites containing NFκB or STAT5 target motifs, and STAT5 or NFκB inhibition prevents GM-CSF production in Ikaros-deficient cells. Importantly, Ikaros also limits GM-CSF production in TCR/CD28-activated human T cells. Our data therefore highlight a critical conserved transcriptional mechanism that antagonizes GM-CSF expression in T cells.
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Dates and versions

hal-03362243 , version 1 (01-10-2021)

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Chiara Bernardi, Gaëtan Maurer, Tao Ye, Patricia Marchal, Bernard Jost, et al.. CD4 + T cells require Ikaros to inhibit their differentiation towards a pathogenic cell fate. Proceedings of the National Academy of Sciences of the United States of America, 2021, 118 (17), pp.e2023172118. ⟨10.1073/pnas.2023172118⟩. ⟨hal-03362243⟩
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