IL-4 prevents adenosine-mediated immunoregulation by inhibiting CD39 expression
Fengqin Fang, Wenqiang Cao, Yunmei Mu, Hirohisa Okuyama, Lingjie Li, Jingtao Qiu, Cornelia M. Weyand, Jörg J. Goronzy
Fengqin Fang, Wenqiang Cao, Yunmei Mu, Hirohisa Okuyama, Lingjie Li, Jingtao Qiu, Cornelia M. Weyand, Jörg J. Goronzy
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Research Article Aging

IL-4 prevents adenosine-mediated immunoregulation by inhibiting CD39 expression

Abstract

The ectonucleotidase CD39 functions as a checkpoint in purinergic signaling on effector T cells. By depleting eATP and initiating the generation of adenosine, it impairs memory cell development and contributes to T cell exhaustion, thereby causing defective tumor immunity and deficient T cell responses in older adults who have increased CD39 expression. Tuning enzymatic activity of CD39 and targeting the transcriptional regulation of ENTPD1 can be used to modulate purinergic signaling. Here, we describe that STAT6 phosphorylation downstream of IL-4 signaling represses CD39 expression on activated T cells by inducing a transcription factor network including GATA3, GFI1, and YY1. GATA3 suppresses ENTPD1 transcription through prevention of RUNX3 recruitment to the ENTPD1 promoter. Conversely, pharmacological STAT6 inhibition decreases T cell effector functions via increased CD39 expression, resulting in the defective signaling of P2X receptors by ATP and stimulation of A2A receptors by adenosine. Our studies suggest that inhibiting the STAT6 pathway to increase CD39 expression has the potential to treat autoimmune disease while stimulation of the pathway could improve T cell immunity.

Authors

Fengqin Fang, Wenqiang Cao, Yunmei Mu, Hirohisa Okuyama, Lingjie Li, Jingtao Qiu, Cornelia M. Weyand, Jörg J. Goronzy

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Figure 6

STAT6 inhibition suppresses T cell function through CD39 upregulation.

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STAT6 inhibition suppresses T cell function through CD39 upregulation. (...
(A and B) T cells were stimulated in the absence or presence of the STAT6 inhibitor AS1517499 (100 nM for A) or 20 ng/mL IL-4 for B. Cells were resuspended in medium supplemented with ATP at 20 μM on day 4 and eATP concentrations were determined after 30 minutes and 1 hour. Results are shown as a percent decline from original concentration. (C) Purified T cells were activated for 4 days in the absence or presence of AS1517499, then restimulated with newly added Dynabeads for 6 hours before cells were collected for intracellular cytokine staining and flow cytometry analysis. (D–F) Day 4-activated T cells were restimulated with newly added Dynabeads plus/minus adenosine (500 μM for D), or the A2AR agonist CGS21680 (100 nM for E), or the P2RX antagonist oATP (100 μM for F) for 6 hours and then stained for intracellular cytokines. (G) Purified T cells were treated with STAT6 inhibitor AS1517499, A2AR antagonist SCH58621, or both during T cell activation by Dynabeads. On day 4, cells were restimulated by PMA/IONO for 4 hours before being collected for intracellular cytokine staining. Results are pooled from 3 experiments. Data in C are shown as mean ± SEM and compared by paired 2-tailed Student’s t test in A–G.