Extracellular adenosine regulates naive T cell development and peripheral maintenance

• Published in: The Journal of experimental medicine 2013-11, Vol.210 (12), p.2693-2706
• Main Authors: Cekic, Caglar, Sag, Duygu, Day, Yuan-Ji, Linden, Joel
• Format: Article
• Language: English
• Subjects: Adenosine - metabolism; Animals; Apoptosis; Cell Differentiation; Cell Proliferation; Cell Survival; Cyclic AMP-Dependent Protein Kinases - metabolism; Extracellular Space - metabolism; Female; Gene Expression Regulation; Immunologic Memory; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Receptor, Adenosine A2A - deficiency; Receptor, Adenosine A2A - genetics; Receptor, Adenosine A2A - metabolism; Receptors, Antigen, T-Cell - metabolism; Receptors, Interleukin-7 - genetics; Receptors, Interleukin-7 - metabolism; Signal Transduction; T-Lymphocytes - cytology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20130249

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 A2A receptor (A2AR) gene, Adora2a, and show that either global A2AR deletion or cre-mediated T cell deletion elicits a decline in the number of naive but not memory T cells. A2AR 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, A2AR 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, A2AR signaling regulates T cell development and maintenance to sustain normal numbers of naive T cells in the periphery.