Cell-intrinsic adenosine A2A receptor signaling is required for T cell homeostasis and control of tumor growth (47.1)

Abstract

Abstract Adenosine generated as a result of normal metabolic activity is elevated in response to tissue stress, damage, or hypoxia. By stimulating adenosine A2A receptors (A2ARs) adenosine links metabolic activity to regulation of normal physiological functions such as sleep, blood flow, and inflammation. Although stimulation of A2ARs on activated T cells and APCs acutely suppresses inflammation and immune killing of tumor cells, global A2AR deletion has variable effects on the growth rate of syngeneic tumors, suggesting that A2AR signaling has opposing effects on immune function. Here we show that A2ARs are required for homeostatic maintenance of naïve T cells. In global A2AR-deficient mice naïve T cells undergo apoptosis, which drastically lower their number in blood and in peripheral lymph nodes. Lymphoid deletion of A2ARs, adoptive co-transfer and mixed bone-marrow reconstitution experiments showed that cell intrinsic A2AR signaling is required for T cell homeostasis. A2AR signaling is also required for interleukin 7 to optimally facilitate T cell survival ex vivo. In mice injected with syngeneic melanoma cells, lymphoid-specific A2AR deletion decreases T cell numbers in the periphery and in the tumor, reduces the proportion of tumor infiltrating T cells with an activated/memory phenotype, and markedly accelerates tumor growth. The results indicate that homeostatic adenosine production and A2AR signaling are required in naïve T cell maintenance and immune defense against tumors.