IL-27 confers a protumorigenic activity of regulatory T cells via CD39

Expression of ectonucleotidase CD39 contributes to the suppressive activity of Foxp3⁺ regulatory T cells (Tregs) by hydrolyzing immunogenic ATP into AMP. The molecular mechanism that drives CD39 expression on Tregs remains elusive. We found that tumor-infiltrating Tregs (Ti-Tregs) failed to up-regul...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2019-02, Vol.116 (8), p.3106-3111
Main Authors: Park, Young-Jun, Ryu, Heeju, Choi, Garam, Kim, Byung-Seok, Hwang, Eun Sook, Kim, Hun Sik, Chung, Yeonseok
Format: Article
Language:English
Subjects:
Animals
Antigens, CD - genetics
Apyrase - genetics
Biological Sciences
Bone marrow
Carcinogenesis - genetics
CD8 antigen
Ectonucleotidase
Forkhead Transcription Factors - genetics
Foxp3 protein
Gene Expression Regulation, Neoplastic
Humans
Immunity
Immunogenicity
Immunoregulation
Interleukin 27
Interleukin-27 - genetics
Lymphocytes
Lymphocytes T
Mice
Signaling
Stat1 protein
STAT1 Transcription Factor - genetics
Stat3 protein
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - metabolism
Th17 Cells
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Summary:Expression of ectonucleotidase CD39 contributes to the suppressive activity of Foxp3⁺ regulatory T cells (Tregs) by hydrolyzing immunogenic ATP into AMP. The molecular mechanism that drives CD39 expression on Tregs remains elusive. We found that tumor-infiltrating Tregs (Ti-Tregs) failed to up-regulate CD39 in mice lacking EBI3 subunit of IL-27 or IL-27Ra. Mixed bone marrow chimera and in vitro studies showed that IL-27 signaling in Tregs directly drives CD39 expression on Ti-Tregs in a STAT1-dependent, but STAT3- and T-bet–independent, manner. Tregs stimulated with IL-27 showed enhanced suppressive activities against CD8⁺ T cell responses in vitro. Moreover, IL-27Ra–deficient Tregs and STAT1-deficient Tregs were less efficient than WT Tregs in suppressing antitumor immunity in vivo. CD39 inhibition significantly abolished IL-27–induced suppressive activities of Tregs. Thus, IL-27 signaling in Tregs critically contributes to protumorigenic properties of Tregs via up-regulation of CD39.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1810254116