TNFR2 ligation in human T regulatory cells enhances IL2-induced cell proliferation through the non-canonical NF-κB pathway.
Al-Lamki, Rafia S
Pober, Jordan S
Bradley, John R
Springer Science and Business Media LLC
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Wang, J., Ferreira, R., Lu, W., Farrow, S., Downes, K., Jermutus, L., Minter, R., et al. (2018). TNFR2 ligation in human T regulatory cells enhances IL2-induced cell proliferation through the non-canonical NF-κB pathway.. Sci Rep, 8 (1), 12079. https://doi.org/10.1038/s41598-018-30621-4
Human T regulatory cells (T regs) express high levels of TNF receptor 2 (TNFR2). Ligation of TNFR2 with TNF, which can recognise both TNFR1 and TNFR2, or with a TNFR2-selective binding molecule, DARPin 18 (D18) activates canonical NF-κB signalling, assessed by IκBα degradation, and the magnitude of the response correlates with the level of TNFR2 expression. RNA-seq analysis of TNF- or D18-treated human T regs revealed that TNFR2 ligation induces transcription of NFKB2 and RELB, encoding proteins that form the non-canonical NF-κB transcription factor. In combination with IL2, D18 treatment is specific for T regs in (1) stabilising NF-κB-inducing kinase protein, the activator of non-canonical NF-κB signalling, (2) inducing translocation of RelB from cytosol to nucleus, (3) increasing cell cycle entry, and (4) increasing cell numbers. However, the regulatory function of the expanded T regs is unaltered. Inhibition of RelB nuclear translocation blocks the proliferative response. We conclude that ligation of TNFR2 by D18 enhances IL2-induced T regs proliferation and expansion in cell number through the non-canonical NF-κB pathway.
Cell Nucleus, Cell Proliferation, Cells, Cultured, Gene Expression Regulation, Healthy Volunteers, Humans, Interleukin-2, NF-KappaB Inhibitor alpha, NF-kappa B p52 Subunit, Primary Cell Culture, Proteolysis, Receptors, Tumor Necrosis Factor, Type II, Recombinant Fusion Proteins, Signal Transduction, T-Lymphocytes, Regulatory, Transcription Factor RelB
External DOI: https://doi.org/10.1038/s41598-018-30621-4
This record's URL: https://www.repository.cam.ac.uk/handle/1810/279956
Attribution 4.0 International (CC BY 4.0)
Licence URL: https://creativecommons.org/licenses/by/4.0/
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