Whole Body Irradiation (WBI) impairs antigen-independent functions of memory CD8 T cells 2255916

Abstract

Abstract Introduction Radiation exposure is increasing due to its expanding use in the medical, energy production, and space travel industries. It has adverse effects on the memory CD8 T cell compartment, including permanent numerical loss, reduced cytokine production following antigen (Ag) stimulation, and diminished proliferative capacity upon in vivo challenge. However, it remains unclear how WBI affects bystander function of memory CD8 T cells (non-Ag-driven IFNγ production) and their trafficking to sites of inflammation. Here we define how radiation exposure impacts memory CD8 T cell sensing and responsiveness to inflammatory cues in the environment. Methods 1M P14 CD8 T cells from control (0 Gy) or irradiated (5 Gy) mice were subjected to scRNA-seq to analyze expression of cytokine/chemokine receptors and signaling-related genes. To evaluate how this transcriptional profile translated to functional bystander activation, mice containing 1M and quaternary (4M) P14 CD8 T cells were exposed to either 5 Gy or 0 Gy WBI, then challenged with virulent L. monocytogenes (LM) lacking gp33 expression at different days post-WBI. Spleens were harvested 20 hrs post-infection and incubated with brefeldin A (BFA) for one hour prior to intracellular staining. Results Pathway analysis of scRNA-seq data revealed differential expression of genes involved in cytokine sensing/signaling in irradiated 1M P14 CD8 T cells. Consistent with this, both 1M and 4M CD8 T cells from irradiated mice produced significantly less IFNγ and exhibited reduced expression of activation markers CD25 and CD69 following LM infection, despite higher bacterial burdens in vivo. Conclusion Collectively, data demonstrate that irradiation impairs the bystander functions of both 1M and 4M CD8 T cells. Together with previous observations showing radiation-induced inhibition of Ag-specific responses, our results highlight a multifaceted disruption of memory CD8 T cell immunity–insights that are critical for the development of effective post-radiation therapies. Funding Source n/a Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)