Extracellular adenosine regulates naive T cell development and peripheral maintenance

Adenosine produced as a byproduct of metabolic activity is present in all tissues and produces dose-dependent suppression of TCR signaling. Naive T cell maintenance depends on inhibition of TCR signals by environmental sensors, which are yet to be fully defined. We produced mice with a floxed adenosine A(2A) receptor (A(2A)R) gene, Adora2a, and show that either global A(2A)R deletion or cre-mediated T cell deletion elicits a decline in the number of naive but not memory T cells. A(2A)R signaling maintains naive T cells in a quiescent state by inhibiting TCR-induced activation of the phosphatidylinositide 3-kinase (PI3K)–AKT pathway, thereby reducing IL-7Rα down-regulation and naive T cell apoptosis. Patterns of IL-7Rα expression on T cells in chimeric mice reconstituted with Adora2a(+/+) and Adora2a(−/−) bone marrow cells suggest that decreased IL-7Rα in naive T cells is a cell-intrinsic consequence of Adora2a deletion. In addition, A(2A)R expression increases in early thymic T cell development and contributes to progression of double-negative thymic precursors to single-positive thymocytes with increased IL-7Rα expression. Therefore, A(2A)R signaling regulates T cell development and maintenance to sustain normal numbers of naive T cells in the periphery.