Low-dose γ-rays modify CD4⁺ T cell signalling response to simulated solar particle event protons in a mouse model

Abstract

Purpose:  Astronauts on missions are exposed to low-dose/low-dose-rate (LDR) radiation and could receive high doses during solar particle events (SPE). This study investigated T cell function in response to LDR radiation and simulated SPE (sSPE) protons, alone and in combination.

Materials and methods:  C57BL/6 mice received LDR γ-radiation (⁵⁷Co) to a total dose of 0.01 Gray (Gy) at 0.179 mGy/h, either with or without subsequent exposure to 1.7 Gy sSPE protons delivered over 36 h. Mice were euthanised on days 4 and 21 post-exposure. T cells with cluster of differentiation 4 (CD4⁺) were negatively isolated from spleens and activated with anti-CD3 antibody. Cells and supernatants were evaluated for survival/signalling proteins and cytokines.

Results:  The most striking effects were noted on day 21. In the survival pathway, nuclear factor-kappaB (NF-κB; total and active forms) and p38 mitogen activated protein kinase (p38MAPK; total) were significantly increased and cJun N-terminal kinase (JNK; total and active) was decreased when mice were primed with LDR γ-rays prior to sSPE exposure (P < 0.001). Evaluation of the T cell antigen receptor (TCR) signalling pathway revealed that LDR γ-ray exposure normalised the high sSPE proton-induced level of lymphocyte specific protein tyrosine kinase (Lck; total and active) on day 21 (P < 0.001 for sSPE vs. LDR + sSPE), while radiation had no effect on active zeta-chain-associated protein kinase 70 (Zap-70). There was increased production of interleukin-2 (IL-2) and IL-4 and decreased transforming growth factor-β1 in the LDR + sSPE group compared to the sSPE group.

Conclusion:  The data demonstrate, for the first time, that protracted exposure to LDR γ-rays can significantly modify the effects of sSPE protons on critical survival/signalling proteins and immunomodulatory cytokines produced by CD4⁺ T cells.

Keywords:

• particle radiation
• solar flare
• T lymphocytes
• signalling pathways
• cytokines

Acknowledgements

The authors thank Melba L. Andres and Steve Rightnar for assistance in biological assays and g-radiation dosimetry. Also, the expert advice and assistance of Dr George B. Coutrakon, Peter Koss, and engineers at Optivus Technology, Inc. needed for execution of sSPE protons is greatly appreciated. We would also like to thank Ingenuity Pathways Analysis (Ingenuity® Systems, www.ingenuity.com) from which we derived information to design the survival/signalling pathway interactions (Figure 7). This study was supported by the Low Dose Radiation Research Program, Office of Science, U.S. Department of Energy Grant No. DE-FG02-05ER64098, NASA grant NNJ06HD78A, and the LLUMC Department of Radiation Medicine.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.