RRC ID 82739
Author Concepcion AR, Wagner LE 2nd, Zhu J, Tao AY, Yang J, Khodadadi-Jamayran A, Wang YH, Liu M, Rose RE, Jones DR, Coetzee WA, Yule DI, Feske S.
Title The volume-regulated anion channel LRRC8C suppresses T cell function by regulating cyclic dinucleotide transport and STING-p53 signaling.
Journal Nat Immunol
Abstract The volume-regulated anion channel (VRAC) is formed by LRRC8 proteins and is responsible for the regulatory volume decrease (RVD) after hypotonic cell swelling. Besides chloride, VRAC transports other molecules, for example, immunomodulatory cyclic dinucleotides (CDNs) including 2'3'cGAMP. Here, we identify LRRC8C as a critical component of VRAC in T cells, where its deletion abolishes VRAC currents and RVD. T cells of Lrrc8c-/- mice have increased cell cycle progression, proliferation, survival, Ca2+ influx and cytokine production-a phenotype associated with downmodulation of p53 signaling. Mechanistically, LRRC8C mediates the transport of 2'3'cGAMP in T cells, resulting in STING and p53 activation. Inhibition of STING recapitulates the phenotype of LRRC8C-deficient T cells, whereas overexpression of p53 inhibits their enhanced T cell function. Lrrc8c-/- mice have exacerbated T cell-dependent immune responses, including immunity to influenza A virus infection and experimental autoimmune encephalomyelitis. Our results identify cGAMP uptake through LRRC8C and STING-p53 signaling as a new inhibitory signaling pathway in T cells and adaptive immunity.
Volume 23(2)
Pages 287-302
Published 2022-2-1
DOI 10.1038/s41590-021-01105-x
PII 10.1038/s41590-021-01105-x
PMID 35105987
PMC PMC8991407
MeSH Animals Anions / metabolism* Calcium / metabolism Dinucleoside Phosphates / metabolism* Female Ion Channels / metabolism* Membrane Proteins / metabolism* Mice Mice, Inbred C57BL Nucleotides, Cyclic / metabolism Signal Transduction / physiology T-Lymphocytes / metabolism* Tumor Suppressor Protein p53 / metabolism*
Resource
Mice RBRC05143