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

Proc Natl Acad Sci U S A. 2021 Apr 27;118(17):e2023172118. doi: 10.1073/pnas.2023172118.


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.

Keywords: GM-CSF; IL-17; Ikaros; pathogenicity; proinflammatory cytokines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*


  • CSF2 protein, human
  • IKZF1 protein, human
  • Ikaros Transcription Factor
  • Granulocyte-Macrophage Colony-Stimulating Factor