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

Abstract

CD4+Foxp3+ regulatory T cells (Tregs) are pivotal for the inhibition of autoimmune inflammatory responses. One way to therapeutically harness the immunosuppressive actions of Tregs is to stimulate the proliferative expansion of TNFR2-expressing CD4+Foxp3+ Tregs 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 Tregs in a tmTNF/TNFR2-dependent manner. In a mouse colitis model, inhibition of TPCs by tetrandrine markedly attenuates colon inflammation by expansion of Tregs. 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 Tregs and elucidate the basis of clinical use in the treatment of autoimmune and other inflammatory diseases.

The role of CD4+FoxP3+ regulatory T cells in the immunopathogenesis of COVID-19: implications for treatment

“…Tetrandrine is a known blocker of the two-pore channel, and this property of tetrandrine can inhibit the host cell entrance of ebola virus, MERS-CoV, and SARS-CoV-2 spike protein pseudovirions [142][143][144]. Recently, we reported that inhibition of the two-pore channel in APC by tetrandrine enhanced the expression of mTNF on APC and consequently induced the proliferative expansion of Tregs via TNFR2 signaling [145,146]. Further, we also found that tetrandrine potently inhibited the differentiation of Th1, Th2 and Th17 cells, while sparing the differentiation of Treg cells [139].…”

Topical Application of Tetrandrine Nanoemulsion Promotes the Expansion of CD4+Foxp3+ Regulatory T Cells and Alleviates Imiquimod-Induced Psoriasis in Mice

“…Previously, we showed that TET inhibited colitis through Tregs in TNFR2 dependent manner ( 13 ). To assess if this amelioration from psoriasis-like skin inflammation after TET NE treatment ( Figure 4 ) was attributed to TNFR2 expression, WT, or TNFR1 -/- or TNFR2 -/- mice were treated with IMQ daily for 6 days.…”

“…Thus, boosting the Tregs function in psoriasis patients has the potential to alleviate psoriasis. Strikingly, our previous work has demonstrated that TET, a traditional Chinese medicine-derived small compound could promote Tregs expansion by enhancing tmTNF expression on antigen-presenting cells through tmTNF/TNFR2 signaling in vivo ( 13 ). Simultaneously, TET did not promote or inhibit the in vitro generation of iTregs ( 12 ).…”

“…Furthermore, we have shown that TET inhibited the release of soluble TNF (sTNF) while enhanced transmembrane TNF (tmTNF) expression on antigen-presenting cells and consequently promotes the expansion of Tregs through tmTNF/TNFR2-dependent manner. This mechanism is attributable to the anti-inflammatory effect of TET in mouse colitis model ( 13 ). To therapeutically harness this property of TET while reducing potential toxicity caused by systemic delivery, we examined the effect of topical application of TET on skin inflammation.…”

TNFR2: Role in Cancer Immunology and Immunotherapy

“…Using the mice colitis model, we showed that the expanded Tregs are attributable to the reduced colon inflammation after tetrandrine treatment. [49][50][51] Furthermore, TNFR2 is closely associated with the immunosuppressive function of Treg cells, and the expression of TNFR2 can define the highly suppressive subset of Tregs. 22,25,46,52 Moreover, the number of Tregs in TNFR2 −/− mice is markedly lower than in wild-type (WT) mice, and when stimulated with the septic challenge, they fail to expand.…”