Foxp3-mediated blockage of ryanodine receptor 2 underlies contact-based suppression by regulatory T cells

J Clin Invest. 2023 Dec 15;133(24):e163470. doi: 10.1172/JCI163470.


The suppression mechanism of Tregs remains an intensely investigated topic. As our focus has shifted toward a model centered on indirect inhibition of DCs, a universally applicable effector mechanism controlled by the transcription factor forkhead box P3 (Foxp3) expression has not been found. Here, we report that Foxp3 blocked the transcription of ER Ca2+-release channel ryanodine receptor 2 (RyR2). Reduced RyR2 shut down basal Ca2+ oscillation in Tregs, which reduced m-calpain activities that are needed for T cells to disengage from DCs, suggesting a persistent blockage of DC antigen presentation. RyR2 deficiency rendered the CD4+ T cell pool immune suppressive and caused it to behave in the same manner as Foxp3+ Tregs in viral infection, asthma, hypersensitivity, colitis, and tumor development. In the absence of Foxp3, Ryr2-deficient CD4+ T cells rescued the systemic autoimmunity associated with scurfy mice. Therefore, Foxp3-mediated Ca2+ signaling inhibition may be a central effector mechanism of Treg immune suppression.

Keywords: Antigen-presenting cells; Autoimmunity; Immunology; Tolerance.

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes
  • Calcium / metabolism
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation
  • Mice
  • Ryanodine Receptor Calcium Release Channel* / genetics
  • Ryanodine Receptor Calcium Release Channel* / metabolism
  • T-Lymphocytes, Regulatory*


  • Calcium
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Ryanodine Receptor Calcium Release Channel
  • ryanodine receptor 2. mouse