Hypoxia can suppress T cell activation in a mechanism independent of A2A adenosine receptor (46.27)

Abstract

Abstract Tissue hypoxia plays a key role in the establishment of immunosuppressive environment in vivo, most notably in tumors. Hypoxia promotes local increase of extracellular adenosine, and interaction of adenosine with A2A adenosine receptor (A2AR) strongly inhibits immune activation. The adenosine-A2AR pathway may represent a mechanism of the physiological immunoregulation initiated by hypoxia. However, in this study, we found that hypoxia can also exert its T cell inhibitory effects even in the absence of A2AR. When mouse T cells were activated by anti-CD3 mAb, hypoxia (1% oxygen) strongly impaired T cell activation. Hypoxia showed the same degree of inhibition against wild-type and A2AR-deficient T cells suggesting that hypoxia could inhibit T cells in an A2AR-independent mechanism. In comparison to A2AR stimulation, this A2AR-independent pathway strongly inhibited cell proliferation and cytotoxicity, while IFN-γ-producing activity was more susceptible to A2AR stimulation. In contrast to sustained functional impairment in T cells after A2AR stimulation, T cells activated under hypoxia immediately recovered from the immunosuppressed state and produced high levels of IFN-γ upon restimulation. Although previous in vivo studies have shown the A2AR-dependent immunosuppression by hypoxia, the current study suggests the involvement of multiple different mechanisms in T cell inhibition by hypoxia.