Selective depletion of CD4+CD25+Foxp3+ regulatory T cells by low-dose cyclophosphamide is explained by reduced intracellular ATP levels (100.23)

Abstract

Abstract Adenosine-5'-triphosphate (ATP), the energy molecule and signal element, significantly affects nearly all major biological processes of T cells. Recently, CD4+CD25+Foxp3+ regulatory T (Treg) cells have been demonstrated to play important roles in mediating cancer development and viral infections. Although Cyclophosphamide (CY) has shown promise as a drug to selectively target Treg cells with low-dose in vivo, the underlying molecular mechanism of this selective effect remains unclear. In this report, we provide evidence that the low intracellular ATP concentration accounts for the selective depletion of Treg cells by low-dose CY. Compared to conventional T cells, much lower ATP levels were found in Treg cells. This was due to low expression of one microRNA, miR-142-3p, leading to high adenylyl cyclase 9 to convert more ATP to cAMP, and CD39 on the surface of Treg cells to hydrolyze ATP. As a result, the low level of ATP attenuates the synthesis of glutathione, leading to the decrease of CY detoxification, thus increasing the sensitivity of Treg cells to low-dose CY. Thus, we here identify a molecular pathway through which low-dose cyclophosphamide selectively ablates Treg cells. Our findings also imply that low levels of ATP are probably related to Treg cell function.