Purpose: To evaluate the effect of ionizing radiation (IR) exposure on differentiation and maturation of dendritic cells (DC).

Materials and methods: Bone marrow progenitor cells irradiated in vitro or isolated from mice exposed to whole body or localized tumor irradiation were differentiated into DC. Phenotypic maturation of DC was characterized by labeling with specific antibodies and flow cytometry analysis. Cytokines were estimated by ELISA.

Results: Splenic and bone marrow-derived DC (BMDC) from tumor-bearing mice exposed to localized irradiation showed abrogation of tumor-induced immunosuppression. This was not due to the effect of radiation on tumor cells as DC derived from normal mice exposed to whole-body irradiation (WBI) also showed increase in immune-activating potential of DC. This was observed in terms of increased phenotypic and functional activation of DCs. This phenomenon was also recapitulated if DC were differentiated from in vitro irradiated progenitor cells and was found to be due to STAT5/Zbtb46 signaling mediated by the irradiation-induced apoptotic bodies (ABs). When these ABs were depleted using annexin-beads, these effects were reversed confirming the involvement of this pathway. The role of ABs was further validated in DC derived from mice exposed to WBI in adaptive response experiments with 0.1 Gy priming dose prior to 2 Gy challenge dose. A corresponding reduction in DC maturation markers was observed with decrease in apoptosis in vivo. Further, these DCs derived from irradiated progenitors (IP) could resist the suppressive effects of tumor conditioned medium (TCM) and had increased immune-activating potential as seen in the tumor-bearing mice.

Conclusions: Though radiation is the most commonly used therapeutic modality for cancer, its effects on dendritic cell differentiation is not completely understood. We demonstrate here for the first time that exposure to select doses of IR can increase immune-activating potential of DC through ABs. This can have implications in selection of appropriate doses of IR during radiotherapy of cancer patients.

目的：评估电离辐射（IR）对树突状细胞（DC）分化和成熟的影响。

材料和方法：体外照射或从暴露于全身或局部肿瘤照射的小鼠中分离的骨髓祖细胞分化为DC。DC的表型成熟通过用特异性抗体标记和流式细胞术分析来表征。通过ELISA估计细胞因子。

结果：暴露于局部辐射的荷瘤小鼠的脾脏和骨髓来源的DC（BMDC）显示，肿瘤诱导的免疫抑制被取消。这不是由于放射线对肿瘤细胞的影响，因为来自暴露于全身照射（WBI）的正常小鼠的DC也显示出DC的免疫激活电位增加。观察到DC的表型和功能激活增加。如果DC从体外照射的祖细胞中分化出来，这种现象也会被重述，并且被发现是由于辐射诱导的凋亡小体（ABs）介导的STAT5 / Zbtb46信号传导。当使用膜联蛋白珠消除这些AB时，这些作用被逆转，证实了该途径的参与。在2 Gy激发剂量之前的0.1 Gy引发剂量的适应性反应实验中，在暴露于WBI的小鼠的DC中进一步验证了ABs的作用。观察到DC成熟标志物相应减少，体内凋亡减少。此外，这些源自辐射祖细胞（IP）的DC可以抵抗肿瘤条件培养基（TCM）的抑制作用，并具有更高的免疫激活潜能，如在荷瘤小鼠中所见。

结论：尽管放射线是最常用的癌症治疗方法，但其对树突状细胞分化的影响尚不完全清楚。我们在这里首次证明，选择剂量的IR暴露可以增加通过ABs激活DC的免疫活性。这可能对癌症患者放疗期间选择合适的IR剂量有影响。