FoxP3-mediated blockage of ryanodine receptor 2 is the molecular basis for the contact-based suppression by regulatory T cells

Abstract

The suppression mechanism of regulatory T cells is an intensely investigated topic. As our focus has shifted towards a model centered on indirect inhibition of dendritic cells, a universally applicable effector mechanism controlled by FoxP3 expression has not been found. Here, we report that FoxP3 blocks the transcription of ER Ca²⁺-release channel ryanodine receptor 2. Reduced RyR2 shuts down basal Ca²⁺ oscillation in Tregs, which reduces m-Calpain activities that is needed for T cells to disengage from DCs, suggesting a persistent blockage of DC antigen presentation. RyR2 deficiency renders the CD4⁺ T cell pool to become immune suppressive, and 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 rescue the systemic autoimmunity associated with Scurfy mice. Therefore, FoxP3-mediated Ca²⁺ signaling inhibition may be a central effector mechanism of Treg immune suppression.