Abstract
The ectonucleotidase CD39 on human regulatory T‐cells (Treg) is an important immune regulator which is dysregulated in autoimmune diseases and cancer immunosuppression. We here define that CD39 expression on Treg is independent of the Treg‐specific transcription factors FOXP3 and HELIOS and promoted by canonical TGF‐b‐ and mTOR‐signaling. Furthermore, the TGF‐b mediated upregulation of CD39 is counteracted by reactive oxygen species (ROS)‐driven autophagy. In line, CD39+ peripheral blood Treg constitute a distinct lineage with low autophagic flux and absent ROS production. Patients with rare genetic defects in autophagy show supraphysiological levels of CD39+ Treg, validating our observations in vivo. These biological processes rely on a distinct transcriptional program with CD39+ Treg expressing low levels of two genes with putative involvement in autophagy, NEFL and PLAC8. Furthermore, the TGF‐b downstream transcription factor SOX4 is selectively upregulated in CD39+ Treg. Overexpression of SOX4 in Treg strongly increases CD39 expression, while Crispr/Cas9‐mediated knockout of SOX4 in Treg has the opposing effect. Thus, we identify a crucial role of SOX4 in immune regulation and provide new insights involving the interplay of tolerogenic cues and autophagy in Treg.
Highlights
The immune system involves highly regulated processes with activating and suppressive signals keeping each other in balance
We identified strong downregulation of the TGF-b signaling inhibitor PMEPA162 and significant upregulation of the TGF-b downstream transcription factor SOX4.63 two genes with putative involvement in autophagy, NEFL64 and PLAC865 were strongly downregulated in CD39+ thymus-derived Treg (tTreg) (Figure 8A)
The ATP-degrading ectonucleotidase CD39 plays an important role in the regulation of immune responses under physiological conditions
Summary
The immune system involves highly regulated processes with activating and suppressive signals keeping each other in balance. In contrast to murine tTreg, human tTreg do not uniformly express CD39.13 Recent studies have defined that expression of CD39 segregates human tTreg into two subpopulations which show a high interindividual variability.[13,18,19] These two subsets are functionally distinct, as CD39+ tTreg display higher suppressive capacity, especially regarding the suppression of IFN-g and IL-17 production by effector T-cells.[18]. While autophagy is pivotal for energy supply and cell homeostasis, the autophagy status feeds back into many important cellular processes such as differentiation and survival.[32,33] In this context, a growing number of studies have described links between autophagy and the development and function of immune cells.[34,35]. In this study, we addressed the functional interplay of tolerogenic signals, ROS production and autophagy in in vitro induced Treg and peripheral blood tTreg from healthy donors in the regulation of CD39. Transcriptomic comparison of CD39−/CD39+ tTreg were performed to identify potential genetic mechanisms and transcription factors underlying these cellular processes
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