Isolated CD39 Expression on CD4+ T Cells Denotes both Regulatory and Memory Populations

Foxp3⁺ regulatory T cells (Tregs) express both ectoenzymes CD39 and CD73, which in tandem hydrolyze pericellular ATP into adenosine, an immunoinhibitory molecule that contributes to Treg suppressive function. Using Foxp3GFP knockin mice, we noted that the mouse CD4⁺CD39⁺ T‐cell pool contains two roughly equal size Foxp3⁺ and Foxp3^? populations. While Foxp3⁺CD39⁺ cells are CD73^bright and are the bone fide Tregs, Foxp3^?CD39⁺ cells do not have suppressive activity and are CD44⁺CD62L^?CD25^?CD73^dim/?, exhibiting memory cell phenotype. Functionally, CD39 expression on memory and Treg cells confers protection against ATP‐induced apoptosis. Compared with Foxp3^?CD39^? naïve T cells, Foxp3^?CD39⁺ cells freshly isolated from non‐immunized mice express at rest significantly higher levels of mRNA for T‐helper lineage‐specific cytokines IFN‐γ (Th1), IL‐4/IL‐10 (Th2), IL‐17A/F (Th17), as well as pro‐inflammatory cytokines, and rapidly secrete these cytokines upon stimulation. Moreover, the presence of Foxp3^?CD39⁺ cells inhibits TGF‐β induction of Foxp3 in Foxp3^?CD39^? cells. Furthermore, when transferred in vivo, Foxp3^?CD39⁺ cells rejected MHC‐mismatched skin allografts in a much faster tempo than Foxp3^?CD39^? cells. Thus, besides Tregs, CD39 is also expressed on pre‐existing memory T cells of Th1‐, Th2‐ and Th17‐types with heightened alloreactivity.