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

Author:

He, Tianzhen [ORCID]

Yang,De [ORCID]

Li, Xiao-Qing [ORCID]

Jiang, Mengmeng [ORCID]

Islam, Md Sahidul

Chen, Shaokui

Chen, Yibo

Yang, Yang

Chou, Chon-Kit

Trivett,Anna [ORCID]

Oppenheim,Joost [ORCID]

Chen, Xin [ORCID]
Author Address

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR 999078, China., Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, MD, USA., Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China., Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, MD, USA. xchen@umac.mo oppenhej@mail.nih.gov., State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR 999078, China. xchen@umac.mo oppenhej@mail.nih.gov.,

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-a-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. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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