Abstract
The immune system, especially the T cell component, is particularly sensitive to ionization radiation (IR), and
epidemiologic data, such as the A-bomb cohort, have demonstrated dysfunction and perturbed T cell
homeostasis even decades after exposure. While measurable acute effects of radiation on T cell populations
and activation have been observed in vivo and in vitro, the long-term physiologic consequences on T cell
immunity in acute-radiation-syndrome survivors and multi-organ injury mediated by immune dysfunction, as
well as the underlying mechanisms, still have considerable uncertainty. Using a bacterial infection model, we
have recently observed that the pathogen loads were higher in the irradiated mice at months after IR. We can
connect this compromised protective immunity against pathogens with impaired T cell immunity, where we
have reported abnormal immune metabolic reprogramming and perturbations in specific metabolic pathways in
activated T cells after IR. With the growing appreciation of interactions between metabolism and immune cell
function, it is increasingly appreciated that distinct metabolic needs in naïve, effector, and memory T cells
require proper metabolic reprogramming to maintain effective T cell immunity after IR. One aim will be to
dissect metabolic perturbations in T cells in various activation/differentiation stages as they contribute to
pathogen immunity. A bacterial infection murine model will be used to assess the long-lasting effects of IR on
changes on T cell immunity in a physiologic context. We will focus on CD8+ T cells in this study, because CD8+
subpopulations are more sensitive to IR-caused damage than CD4+, and secondly, they are critical for immune
defense against intracellular pathogens, including viruses and bacteria. In addition to altering T cell
metabolism, we expect that IR also induces distinct systemic metabolic changes, including those in lymphoid
tissue and mucosal niche, as shown in our published metabolomic studies. Pro-inflammatory metabolites may
synergize with IR-induced premature senescence and drive a positive feedback loop resulting in multi-organ
injury. In this project we will examine the impact of the senescence-associated inflammatory phenotype on T
cell metabolism and immune functions, and assess interventions using senescent cell ablation approach.
Considering that in a real-life nuclear incident, an exposure to mixed fields of neutrons and photon is highly
likely, we have already observed distinct differences between mixed field metabolic responses compared to
single photon or neutron beams. So we will investigate the late effects of mixed neutron/photon radiation on T
cells’ metabolism. We also plan to address the question how a radiomitigator modulates those IR-caused long-
lasting effects including a senolytic approach. The successful completion of these aims will help to better
understand how radiation causes persistent immune dysfunction in ARS survivors. The new concept of
metabolic perturbations of T cells in specific activation/differentiation stages, e.g., naïve vs memory T cells, will
lay the foundation for strategies for preventative intervention.