Cell Reports
Volume 20, Issue 12, 19 September 2017, Pages 2906-2920
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Article
The TNF Receptor Superfamily-NF-κB Axis Is Critical to Maintain Effector Regulatory T Cells in Lymphoid and Non-lymphoid Tissues

https://doi.org/10.1016/j.celrep.2017.08.068Get rights and content
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Highlights

  • TNFRSF members activate NF-κB/RelA and promote the maintenance of effector Treg cells

  • Ablation of RelA impairs effector Treg cells in lymphoid and non-lymphoid tissues

  • RelA is dispensable for the expression and DNA-binding activity of IRF4 in Treg cells

  • Mutations in RelA binding partner NF-κB1 compromise effector Treg cells in humans

Summary

After exiting the thymus, Foxp3+ regulatory T (Treg) cells undergo further differentiation in the periphery, resulting in the generation of mature, fully suppressive effector (e)Treg cells in a process dependent on TCR signaling and the transcription factor IRF4. Here, we show that tumor necrosis factor receptor superfamily (TNFRSF) signaling plays a crucial role in the development and maintenance of eTreg cells. TNFRSF signaling activated the NF-κB transcription factor RelA, which was required to maintain eTreg cells in lymphoid and non-lymphoid tissues, including RORγt+ Treg cells in the small intestine. In response to TNFRSF signaling, RelA regulated basic cellular processes, including cell survival and proliferation, but was dispensable for IRF4 expression or DNA binding, indicating that both pathways operated independently. Importantly, mutations in the RelA binding partner NF-κB1 compromised eTreg cells in humans, suggesting that the TNFRSF-NF-κB axis was required in a non-redundant manner to maintain eTreg cells in mice and humans.

Keywords

TNFRSF signaling
effector Treg cells
NF-κB/RelA
TCR
IRF4
tissue Treg cells
RORγt+ Treg cells

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