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

摘要

CD4sup+/supFoxp3sup+/sup regulatory T cells (Tsubregs/sub) are pivotal for the inhibition of autoimmune inflammatory responses. One way to therapeutically harness the immunosuppressive actions of Tsubregs/sub is to stimulate the proliferative expansion of TNFR2-expressing CD4sup+/supFoxp3sup+/sup Tsubregs/sub 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 Tsubregs/sub in a tmTNF/TNFR2-dependent manner. In a mouse colitis model, inhibition of TPCs by tetrandrine markedly attenuates colon inflammation by expansion of Tsubregs/sub. Mechanistically, we show that TPC inhibitors enhance tmTNF levels by disrupting surface expression of TNF-α–converting enzyme by regulating vesicle trafficking. These results suggest that the therapeutic potential of TPC inhibitors is mediated by expansion of TNFR2-expressing Tsubregs/sub and elucidate the basis of clinical use in the treatment of autoimmune and other inflammatory diseases.