CD39-deficient T reg cells fail to suppress CD4+ T cells, resulting in skin graft rejection (squares).

Regulatory T (T reg) cells have a new trademark and a new mode of action to go with it. While searching for a mysterious mechanism of T cell suppression, Deaglio et al. (page 1257) have also discovered a new and improved way to identify and purify T reg cells.

Some T reg cells suppress effector T cells by secreting inhibitory cytokines. But this suppression can continue even when cytokine activity is blocked, suggesting that other inhibitory mechanisms exist. Getting to the bottom of this mystery has been difficult due to the lack of cell surface markers that can be used to isolate pure populations of T reg cells for functional assays. CD25, a T reg cell surface receptor, is also expressed on activated T cells. Foxp3, on the other hand, is unique to T reg cells, but is hidden inside them.

While looking for alternate mechanisms of T reg–mediated immune suppression, the team considered two cell surface proteins—CD39 and CD73. CD39 is a surface-attached enzyme that jumpstarts the conversion of extracellular nucleotides such as ATP into AMP; AMP is further degraded by CD73 into adenosine—a known anti-inflammatory molecule that dampens T cell activation.

The team found that T reg cells from CD39-deficient mice were 50–60% less effective in inhibiting the proliferation of effector T cells in vitro and failed to prevent host T cells from rejecting skin grafts in transplantation models. CD39, which was previously not detected on T cells, was now found specifically on Foxp3+ T reg cells along with CD73. These surface proteins thus offer a simpler way to zero in on this hard-to-catch population.