Low-dose radiation (LDR) is usually defined as a low linear energy transfer of less than 0.2 Gy or high linear energy transfer of less than 0.05 Gy. (1,2) In recent years, environmental LDR, especially those with high-energy, including X-ray and γ radiation, has become more and more prevalent due to various factors, such as increased medical imaging and treatments, nuclear power generation, and nuclear waste leakage, as well as some naturally occurring radioactive materials like minerals in the ground. (3,4) High-dose radiation (HDR) like cancer radiotherapy generally requires more than 2 Gy per day, and the severe detrimental effects on the human body were extensively explored, including cell death and tissue damage. (5,6) However, the biological effects of LDR are still highly uncertain.

The immune system plays as one of the most important defense mechanisms against various environmental insultants, including radiation. (7,8) T lymphocytes are the major player in the adaptive immune system, which are divided into CD4+ and CD8+ T cells with their own subsets. Type 1 CD4+ helper T cells (Th1) and type 1 CD8+ cytotoxic T cells (Tc1) are the main immune responsers by producing cytokines that secrete inflammatory cytokines and cytolytic molecules to kill pathogen or malignant cells, while regulatory T cells (Treg) are the immunosuppressive subtype. (9,10) LDR has been shown to interact with the immune system, however, with contradictory findings. Although some studies have found that LDR may suppress the immune system, decrease the thymic function, increase the risk of certain diseases, (11−14) there are many more studies that have shown LDR may induce immune responses in disease models. (15−17) However, the effect of LDR on healthy individuals is still highly obscure, as well as detailed cell subtype of its action, and the underlying molecular mechanisms. To illustrate the unambiguous immunoregulatory effect of environmental LDR, which may also promote both clinical and nonclinical application of LDR, it is critical to obtain the detailed information regarding to the effect of LDR on different immune cell subsets.

Here, we first irradiated splenocytes, the immune cells from largest lymphatic organ, with LDR, and found that the percentage of Th1 cells was specifically upregulated. Mechanistically, we found that LDR induced mitochondrial damage and resulted in the activation of the stimulator of interferon genes (STING) pathway that elevated the expression of T-bet, the master transcriptional factor of Th1-cell differentiation. We also irradiated mice with whole body LDR and found a similar phenomenon. The percentage of differentiated Th1 cells were elevated after LDR. Furthermore, preventive LDR significantly suppressed tumor growth, with increased systemic and intratumoral antitumor immunity, further confirming the immunoregulatory role of LDR. Therefore, our study elaborated in detail on the facilitating effect of low-dose environmental radiation on the human immune system and its underlying mechanism and thus provides novel information for the handling and potential future application of LDR...

Figure 1. Effects of LDR on T cells in vitro. (a) Schematic for the treatment of splenocytes by LDR with or without activation by PMA + ionomycin and the following analysis for flow cytometry. (b,c) Naïve splenocytes were subjected to the indicated doses of LDR, and the percentage of CD4+ and Th1 cells is shown. (d,e) LDR-treated splenocytes were stimulated by PMA and ionomycin for 6 h, and then the percentage of CD4+ and Th1 cells was tested.

Figure 4. Systemic effects of LDR on T cells in vivo. (a) Schematic for testing the effect of LDR on peripheral and splenic T cells in LDR-treated mice for 14 days with or without PMA + ionomycin treatment. (b,c) The percentage of CD4+ and Th1 naïve T cells from blood (b) or spleen (c) in LDR-treated mice is shown. (d,e) The percentage of CD4+ and Th1 T cells from blood (d) or spleen (e) treated by PMA + ionomycin in LDR-treated mice is shown.

Figure 5. Systemic effects of LDR on T cells from tumor-bearing mice. (a) Schematic for testing the effect of LDR on naïve or activated peripheral and splenic T cells in LDR-treated tumor-bearing mice. (b) The tumor growth curve from mice treated with or without LDR is shown (n = 5). Significance was determined by two-way ANOVA analysis; **p < 0.01. (c) The picture of dissected tumors is shown. (d) The tumor weight of the two groups is compared. (e,f) The percentage of CD4+ and Th1 naïve T cells from blood (e) or spleen (f) in LDR-treated tumor-bearing mice is shown. (g,h) The percentage of CD4+ and Th1 T cells from blood (g) or spleen (h) treated by PMA + ionomycin in LDR-treated tumor-bearing mice is shown.

In summary, we have proposed a critical effect of environmental low-dose radiation from ¹³⁷Cs and probably other environmental radioactive nuclides on the immune system, that is, the specific upregulation on inflammatory and tumoridical Th1 immunity. This effect is exerted through the LDR-induced mitochondrial DNA-STING-T-bet pathway. With further study and a more complete understanding of the effect of LDR on human immunity, the handling of radioactive nuclides and the potential application of LDR can be exploited for broader and more effective disease prevention and treatment.