Journal
SCIENTIFIC REPORTS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-018-30621-4
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Funding
- Kidney Research UK
- NIHR Cambridge Biomedical Research Centre
- NIHR BioResource
- NIH
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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, DARP in 18 (D18) activates canonical NF-KB signalling, assessed by hcBoi 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-KB transcription factor. In combination with IL2, D18 treatment is specific for T regs in (1) stabilising NF-kappa B-inducing kinase protein, the activator of non-canonical NF-kappa B signalling, (2) inducing translocation of ReIB 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 ReIB 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-kappa B pathway.
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