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Tumor necrosis factor receptor family costimulation increases regulatory T-cell activation and function via NF-κB

Martina Lubrano di Ricco1, Emilie Ronin1, Davi Collares2

  • 1Sorbonne Université, INSERM, CNRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France.

European Journal of Immunology
|February 4, 2020
PubMed

Insights

Targeting TNF receptor superfamily (TNFRSF) co-stimulation enhances regulatory T cell (Treg) proliferation, survival, and function. This shared mechanism, involving NF-κB, improves Treg-mediated suppression of colitis, impacting therapeutic strategies.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cellular Biology

Background:

  • Tumor Necrosis Factor (TNF) superfamily and TNF receptor superfamily (TNFRSF) drugs are common therapeutics, but their mechanisms are unclear.
  • Foxp3+ regulatory T cells (Tregs) are crucial for immune response modulation.
  • Understanding TNFRSF interactions with Tregs is vital for optimizing immunotherapies.

Purpose of the Study:

  • To investigate the impact of TNFRSF co-stimulation on murine Treg biology.
  • To elucidate the shared signaling pathways involved in TNFRSF-mediated Treg activation.
  • To assess the functional consequences of TNFRSF co-stimulation on Treg-mediated immune suppression.

Main Methods:

  • Co-stimulation of murine Tregs with various TNFRSF members (TNFR2, 4-1BB, GITR, DR3, OX40).
  • Analysis of Treg proliferation, survival, and gene expression patterns.
  • Investigation of downstream signaling pathways, including NF-κB.
  • Assessment of Treg-mediated suppression of colitis in vivo.

Main Results:

  • Engagement of TNFR2, 4-1BB, GITR, and DR3 significantly increased Treg proliferation and survival.
  • TNPSFRSF triggering induced conserved gene expression changes in Tregs, pointing to common signaling pathways.
  • Canonical NF-κB signaling was identified as a key mediator of these effects.
  • TNPSFRSF co-stimulation enhanced Treg-mediated suppression of experimental colitis.

Conclusions:

  • Discrete TNFRSF members converge on shared pathways to enhance Treg activation and function.
  • NF-κB signaling plays a central role in TNFRSF-mediated Treg responses.
  • The therapeutic efficacy of TNFRSF-targeting drugs may be partly attributed to their modulation of Treg activity.
Keywords:
AutoimmunityCostimulationNF-κBRegulatory T cellsTNF receptor family

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