期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2023172118
关键词
Ikaros; GM-CSF; IL-17; proinflammatory cytokines; pathogenicity
资金
- Fondation ARC pour la Recherche sur le Cancer
- Agence Nationale de la Recherche (ANR) [ANR-17-CE15-0023-02]
- Equipe Fondation pour la Recherche Medicale (FRM) [EQU201903007812]
- French State [ANR-10-LABX-0030-INRT, ANR-10-IDEX-0002-02]
- Ligue Regionale contre le Cancer du Grand Est
- FRM [FDM20170637770]
- Ministere de l'Enseignement Superieur, de la Recherche et de l'Innovation
- Agence Nationale de la Recherche (ANR) [ANR-17-CE15-0023] Funding Source: Agence Nationale de la Recherche (ANR)
The transcription factor Ikaros regulates gene expression and chromatin accessibility in T cells to suppress the expression of pathogenic genes, particularly GM-CSF. This mechanism plays a critical role in preventing excessive GM-CSF expression in T cells.
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 NF.B or STAT5 target motifs, and STAT5 or NF kappa B 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 GMCSF expression in T cells.
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