c‐Rel employs multiple mechanisms to promote the thymic development and peripheral function of regulatory T cells in mice

The NF‐κB transcription factor c‐Rel is a critical regulator of Treg ontogeny, controlling multiple points of the stepwise developmental pathway. Here, we found that the thymic Treg defect in c‐Rel‐deficient (cRel–/–) mice is quantitative, not qualitative, based on analyses of TCR repertoire and TCR...

Full description

Saved in:
Bibliographic Details
Published in:European journal of immunology 2021-08, Vol.51 (8), p.2006-2026
Main Authors: Fulford, Thomas S., Grumont, Raelene, Wirasinha, Rushika C., Ellis, Darcy, Barugahare, Adele, Turner, Stephen J., Naeem, Haroon, Powell, David, Lyons, Paul A., Smith, Kenneth G. C., Scheer, Sebastian, Zaph, Colby, Klein, Ulf, Daley, Stephen R., Gerondakis, Steve
Format: Article
Language:English
Subjects:
Cell cycle
Cell cycle progression
Cell proliferation
c‐Rel
Foxp3 protein
Immunoregulation
Lymphocytes T
Lymphopenia
Ontogeny
Regulatory T cells
T cell receptors
Thymic development
Thymus
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The NF‐κB transcription factor c‐Rel is a critical regulator of Treg ontogeny, controlling multiple points of the stepwise developmental pathway. Here, we found that the thymic Treg defect in c‐Rel‐deficient (cRel–/–) mice is quantitative, not qualitative, based on analyses of TCR repertoire and TCR signaling strength. However, these parameters are altered in the thymic Treg‐precursor population, which is also markedly diminished in cRel–/– mice. Moreover, c‐Rel governs the transcriptional programme of both thymic and peripheral Tregs, controlling a core of genes involved with immune signaling, and separately in the periphery, cell cycle progression. Last, the immune suppressive function of peripheral cRel–/– tTregs is diminished in a lymphopenic model of T cell proliferation and is associated with decreased stability of Foxp3 expression. Collectively, we show that c‐Rel is a transcriptional regulator that controls multiple aspects of Treg development, differentiation, and function via distinct mechanisms. c‐Rel controls thymic Treg development by promoting the survival of thymocytes that can become Tregs, augmenting GITRL and IL‐2 signaling, and controlling a transcriptional programme shared by de novo Tregs and tTregs in the periphery. c‐Rel also controls the cell cycle progression, stability, and function of tTregs in the periphery.
ISSN:0014-2980
1521-4141
DOI:10.1002/eji.202048900