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

Thomas S. Fulford, Raelene Grumont, Rushika C. Wirasinha, Darcy Ellis, Adele Barugahare, Stephen J. Turner, Haroon Naeem, David Powell, Paul A. Lyons, Kenneth G.C. Smith, Sebastian Scheer, Colby Zaph, Ulf Klein, Stephen R. Daley, Steve Gerondakis

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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.

Original languageEnglish
Pages (from-to)2006-2026
Number of pages21
JournalEuropean Journal of Immunology
Issue number8
Publication statusPublished - Aug 2021


  • c-Rel
  • Cell cycle progression
  • Regulatory T cells
  • Thymic development

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