The Alternative NF-κB Pathway in Regulatory T Cell Homeostasis and Suppressive Function

J Immunol. 2018 Apr 1;200(7):2362-2371. doi: 10.4049/jimmunol.1800042. Epub 2018 Feb 19.


CD4+Foxp3+ regulatory T cells (Tregs) are essential regulators of immune responses. Perturbation of Treg homeostasis or function can lead to uncontrolled inflammation and autoimmunity. Therefore, understanding the molecular mechanisms involved in Treg biology remains an active area of investigation. It has been shown previously that the NF-κB family of transcription factors, in particular, the canonical pathway subunits, c-Rel and p65, are crucial for the development, maintenance, and function of Tregs. However, the role of the alternative NF-κB pathway components, p100 and RelB, in Treg biology remains unclear. In this article, we show that conditional deletion of the p100 gene, nfkb2, in Tregs, resulted in massive inflammation because of impaired suppressive function of nfkb2-deficient Tregs. Surprisingly, mice lacking RelB in Tregs did not exhibit the same phenotype. Instead, deletion of both relb and nfkb2 rescued the inflammatory phenotype, demonstrating an essential role for p100 as an inhibitor of RelB in Tregs. Our data therefore illustrate a new role for the alternative NF-κB signaling pathway in Tregs that has implications for the understanding of molecular pathways driving tolerance and immunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity / immunology
  • Cell Differentiation
  • Cells, Cultured
  • Endonucleases
  • Immune Tolerance / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B p52 Subunit / genetics*
  • NF-kappa B p52 Subunit / metabolism
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Proto-Oncogene Proteins c-rel / metabolism
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • Transcription Factor RelA / metabolism
  • Transcription Factor RelB / genetics*
  • Transcription Factor RelB / metabolism


  • NF-kappa B p52 Subunit
  • Nfkb2 protein, mouse
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-rel
  • Rela protein, mouse
  • Relb protein, mouse
  • Transcription Factor RelA
  • Transcription Factor RelB
  • Endonucleases
  • Snd1 protein, mouse