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Scientific article
English

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

Publication date2021-04-27
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 Csf2and 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.

eng
Keywords
  • GM-CSF
  • IL-17
  • Ikaros
  • Pathogenicity
  • Proinflammatory cytokines
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Differentiation
  • Cells, Cultured
  • Epigenome
  • Gene Expression Regulation
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Humans
  • Ikaros Transcription Factor / metabolism
  • Lymphocyte Activation
Affiliation Not a UNIGE publication
Citation (ISO format)
BERNARDI, Chiara et al. CD4+ T cells require Ikaros to inhibit their differentiation toward a pathogenic cell fate. In: Proceedings of the National Academy of Sciences of the United States of America, 2021, vol. 118, n° 17, p. e2023172118. doi: 10.1073/pnas.2023172118
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Article (Published version)
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Identifiers
ISSN of the journal0027-8424
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