Abstract
Impairment or stimulation of the immune system by ionizing radiation (IR) impacts on immune surveillance of tumor cells and non-malignant cells and can either foster therapy response or side effects/toxicities of radiation therapy. For a better understanding of the mechanisms by which IR modulates T-cell activation and alters functional properties of these immune cells, we exposed human immortalized Jurkat cells and peripheral blood lymphocytes (PBL) to X-ray doses between 0.1 and 5 Gy. This resulted in cellular responses, which are typically observed also in naïve T-lymphocytes in response of T-cell receptor immune stimulation or mitogens. These responses include oscillations of cytosolic Ca2+, an upregulation of CD25 surface expression, interleukin-2 and interferon-γ synthesis, elevated expression of Ca2+ sensitive K+ channels and an increase in cell diameter. The latter was sensitive to inhibition by the immunosuppressant cyclosporine A, Ca2+ buffer BAPTA-AM, and the CDK1-inhibitor RO3306, indicating the involvement of Ca2+-dependent immune activation and radiation-induced cell cycle arrest. Furthermore, on a functional level, Jurkat and PBL cell adhesion to endothelial cells was increased upon radiation exposure and was highly dependent on an upregulation of integrin beta-1 expression and clustering. In conclusion, we here report that IR impacts on immune activation and functional properties of T-lymphocytes that may have implications in both toxic effects and treatment response to combined radiation and immune therapy in cancer patients.
Highlights
Ionizing irradiation of eukaryotic cells elicits, in addition to DNA damage and damage responses, non-targeted effects, which are mainly related to immune activation and immune functional properties [1, 2]
We have recently reported that an increase of reactive oxygen species (ROS) following X-irradiation of A549 cancer and human embryonic kidney HEK293 cells with doses ≥1 Gy is not restricted to the nucleus but spreads throughout the cell including the cytosol [11]
X-irradiation with single doses ≥2 Gy used in clinical oncological practice generally triggers activating functions to mediate toxic and/or immune stimulatory effects of radiation therapy (RT) [1, 3]
Summary
Ionizing irradiation of eukaryotic cells elicits, in addition to DNA damage and damage responses, non-targeted effects, which are mainly related to immune activation and immune functional properties [1, 2]. In line with that it is well established that Ca2+ signaling cascades play a crucial role in T-cell activation [13,14,15,16] and mediate downstream events like gene expression, entry into the cell cycle and T-cell effector functions. These signaling cascades can be short-circuited by elevating the concentration of free Ca2+ in the cytosol ([Ca2+]cyt) without employing receptor activation [17]
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