Inhibition of two-pore channels in antigen-presenting cells promotes the expansion of TNFR2-expressing CD4+Foxp3+ regulatory T cells

CD4(+)Foxp3(+) regulatory T cells (T-regs) are pivotal for the inhibition of autoimmune inflammatory responses. One way to therapeutically harness the immunosuppressive actions of T-regs is to stimulate the proliferative expansion of TNFR2-expressing CD4(+)Foxp3(+) T-regs via transmembrane TNF (tmTNF). Here, we report that two-pore channel (TPC) inhibitors markedly enhance tmTNF expression on antigen-presenting cells. Furthermore, injection of TPC inhibitors including tetrandrine, or TPC-specific siRNAs in mice, increases the number of T-regs in a tmTNF/TNFR2-dependent manner. In a mouse colitis model, inhibition of TPCs by tetrandrine markedly attenuates colon inflammation by expansion of T-regs. Mechanistically, we show that TPC inhibitors enhance tmTNF levels by disrupting surface expression of TNF-alpha-converting enzyme by regulating vesicle trafficking. These results suggest that the therapeutic potential of TPC inhibitors is mediated by expansion of TNFR2-expressing T-regs and elucidate the basis of clinical use in the treatment of autoimmune and other inflammatory diseases.