Dynamic Foxp3-chromatin interaction controls tunable Treg cell function

Ming-Hong He

doi:10.1084/jem.20232068

Dynamic Foxp3-chromatin interaction controls tunable Treg cell function

2024-06-27

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Mohamed Nadhir Djekidel

DOI：10.1084/jem.20232068

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Abstract

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Nuclear factor Foxp3 determines regulatory T (Treg) cell fate and function via mechanisms that remain unclear. Here, we investigate the nature of Foxp3-mediated gene regulation in suppressing autoimmunity and antitumor immune response. Contrasting with previous models, we find that Foxp3-chromatin binding is regulated by Treg activation states, tumor microenvironment, and antigen and cytokine stimulations. Proteomics studies uncover dynamic proteins within Foxp3 proximity upon TCR or IL-2 receptor signaling in vitro, reflecting intricate interactions among Foxp3, signal transducers, and chromatin. Pharmacological inhibition and genetic knockdown experiments indicate that NFAT and AP-1 protein Batf are required for enhanced Foxp3-chromatin binding in activated Treg cells and tumor-infiltrating Treg cells to modulate target gene expression. Furthermore, mutations at the Foxp3 DNA-binding domain destabilize the Foxp3-chromatin association. These representative settings delineate context-dependent Foxp3-chromatin interaction, suggesting that Foxp3 associates with chromatin by hijacking DNA-binding proteins resulting from Treg activation or differentiation, which is stabilized by direct Foxp3-DNA binding, to dynamically regulate Treg cell function according to immunological contexts.

Keywords:

REGULATORY T-CELLS

NF-KAPPA-B

SYSTEMATIC OPTIMIZATION

TRANSCRIPTION FACTORS

MASS-SPECTROMETRY

GENE-EXPRESSION

TARGET GENES

CIS-ELEMENT

FOXP3

BATF

Dynamic Foxp3-chromatin interaction controls tunable Treg cell function

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