Strengthening bonds via RyR2 inhibition helps immune suppression

Abstract

Foxp3-expressing Tregs employ multiple suppressive mechanisms to curtail conventional T cell (Tconv) responses and establish tissue homeostasis. How Foxp3 coordinates Treg contact-dependent suppressive function is not fully resolved. In this issue of the JCI, Wang and colleagues revealed that Foxp3-mediated inhibition of ryanodine receptor 2 (RyR2) led to strong Treg-DC interactions and enhanced immunosuppression. RyR2 depletion in Tconvs phenocopied this effect and equipped Tconvs with Treg-like suppressive function in multiple inflammatory or autoimmune contexts. This study provides molecular and therapeutic insights underlying how cell-cell contact limits immune reactivity.

Figure 1. RyR2 controls the binding dynamics of Tregs and Tconvs with DCs and its inhibition facilitates immune suppression.

Expression of the sarcoendoplasmic reticulum-localized calcium (Ca²⁺) release channel component RyR2 is high in conventional CD4⁺ T cells (Tconvs). RyR2 contributes to high basal Ca²⁺ oscillations and relatively weak adhesion to DCs, owing to increased m-calpain activation that promotes LFA-1 cleavage and disrupted LFA-1–ICAM-1 interactions. In Tregs, Foxp3 suppresses RyR2 expression, resulting in low basal Ca²⁺ oscillations and downstream m-calpain activity. Consequently, less LFA-1 is cleaved from the Treg surface, and Tregs strongly adhere to DCs via enhanced LFA-1–ICAM-1 interactions. Pharmacological inhibition using JTV519 or shRNA-mediated targeting of RyR2 in Tconvs phenocopies the contact-dependent immunosuppressive effects of Tregs without causing them to adopt a Treg-like program (e.g., Foxp3 expression). Ultimately, low RyR2 levels increase the interactions between Tregs or Tconvs and DCs, thereby promoting immune suppression. Of note, Tregs display higher suppressive function than RyR2-deficient Tconvs, likely due to their capacity to engage both cell contact–dependent and cell contact–independent mechanisms.