What Else Can CD39 Tell Us?

Abstract

As the rate-limiting enzyme in ATP/ADP-AMP-adenosine pathway, CD39 would be a novel checkpoint inhibitor target in preventing adenosine-triggered immune-suppressive effect. In addition, CD39^hi Tregs, but not CD25^hi Tregs, exhibit sustained Foxp3 levels and functional abilities, indicating it could represent a new specific marker of Tregs. Similarly, inhibition of CD39 enzymatic function at the surface of tumor cells alleviates their immunosuppressive activity. Far from conclusive, present research revealed that CD39 also dephosphorylated and thus inactivated self- and pathogen-associated phosphoantigens of Vγ9Vδ2 T cells, which may be the most promising subpopulation for cellular vaccine. CD39 is also tightly related to Th17 cells and can be regarded as a Th17 cells marker. In this review, we focus on present research of CD39 ectoenzyme and provide insights into its clinical application.

Keywords: Bregs; CD161; CD39; Th17 cell; Tregs; adenosine; extracellular ATP; γδ T cell.

Figure 1

Ectoenzymes, e.g., CD39, CD73 mediate the metabolization of extracellular ATP (eATP) to adenosine. eATP signals through P2X and P2Y purinergic receptors to induce inflammation while adenosine exerts immunosuppressive activity on immune cells and thereby protects tissues against excessive inflammation.

Figure 2

Illustration of CD39 function ① eATP accumulates in the extracellular space in response to metabolic stress or cell damage such as apoptosis. ② CD39 initiates extracellular adenosine generation by catalyzing the degradation of ATP and ADP to AMP; CD73 also has ecto-5′-nucleotidase enzyme activity that catalyzes the dephosphorylation of AMP to adenosine; CD39, not CD73, is the rate-limiting enzyme of the cascade leading to the generation of suppressive adenosine. ③ Adenosine activates A2A receptor and subsequently triggers pathways converge on CEBPβ to induce IL10 production. ④ CD39 also dephosphorylates pAgs of Vγ9Vδ2 T cells. This degradation may also be catalyzed by CD39 expressed on Tregs and possibly represents a novel mechanism of Tregs suppressing Vγ9Vδ2 T cells. CD39 upregulation acts as a feedback mechanism to desensitize Vγ9Vδ2 T cells to self- and pathogen-associated pAgs. ⑤ Pro-apoptotic Bim, antiapoptotic Mcl-1, and apoptotic regulators Bax and Bak altogether contribute to T cells homeostasis and survival. Especially, IL-2 and costimulatory signals upregulate Mcl-1 expression and hence allows Tregs to proliferate. We speculate that CD39 is involved in the above signal transduction since CD39 were reported to be associated with T cells apoptosis.

Figure 3

CD39 is involved in Th17 cells expansion and IL-17 secretion and, moreover, CD4⁺CD39⁺CD161⁺ T cells can be regarded as Th17 cells precursors. CD39, combined with CD161, can initiate acid sphingomyelinase enzymatic activity, subsequently, increase intracellular ceramide concentration, then impact STAT3 and mTOR signal transduction, which are essential for Th17 generation and IL-17 secretion.