Mesenchymal Stem Cell-Derived Exosomes Inhibit Stim1–Orai1 Signaling and Calcium Overload-Induced Mitochondrial Damage of Follicular Helper T Cells in Lupus

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by aberrant T cell activity and excessive autoantibody production. Follicular helper T cells (Tfh) play a pivotal role in promoting B cell-mediated autoantibody generation, contributing to SLE progression. Although mesenchymal stem cell-derived exosomes (MSC-Exos) exhibit immunomodulatory properties, their effects on Tfh in SLE and the underlying mechanisms remain unclear. To address this, we first analyzed sorted Tfh from an imiquimod-induced lupus murine model (IMQ-SLE) and found that MSC-Exos effectively suppressed Tfh function. Consistently, Tfh polarization assays demonstrated that MSC-Exos modulate Tfh differentiation in vitro. Subsequently, we evaluated the therapeutic potential of intravenous MSC-Exos administration and confirmed that MSC-Exos markedly inhibited Tfh expansion and function in vivo. Further RNA sequencing followed by validation experiments identified that MSC-Exos restore calcium homeostasis in Tfh. Mechanically, MSC-Exos down-regulate stromal interaction molecule 1 (Stim1) and Orai1 expression, inhibiting nuclear factor of activated T cells (NFAT) and nuclear factor κB (NF-κB) activation. In parallel, MSC-Exos mitigate calcium overload-induced mitochondrial damage by suppressing mitochondrial calcium uniporter (MCU) expression. Finally, we observed that MSC-Exos also promote the differentiation of follicular regulatory T cells (Tfr) both in vivo and in vitro. These findings suggest that MSC-Exos ameliorate SLE by correcting cellular calcium dysregulation and mitochondrial damage in Tfh while simultaneously restoring the Tfh/Tfr imbalance, highlighting their potential as a therapeutic strategy for SLE.