Sublethal whole-body irradiation induces permanent loss and dysfunction in pre-existing pathogen-specific memory CD8 T cell populations

Abstract

Abstract The increasing use of nuclear energy sources inevitably increases the risk of accidental or deliberate radiation-exposure. However, the extent to which radiation-exposure impacts memory CD8 T cells, potent mediators of immunity to recurring intracellular infections and malignancies, remains understudied. Using P14 LCMV immune chimeric mice (P14 chimeras), we observed that sublethal (5Gy) whole body irradiation (WBI) induced a rapid decline in the number of naive (T N) and P14 circulatory memory CD8 T cells (T CIRCM) with the former being more susceptible to radiation-induced death. While T Ncell numbers rapidly recovered, the number of P14 T CIRCMcells remained low at least nine months after radiation-exposure. Additionally, the remaining P14 T CIRCMin irradiated hosts exhibited an inefficient transition to a central memory (CD62L hi) phenotype compared to non-irradiated P14 chimeras. WBI also resulted in long-lasting T-cell intrinsic deficits including diminished cytokine and chemokine production in response to antigen-stimulation along with impaired secondary expansion upon cognate Ag re-encounter. Irradiated P14 chimeras displayed significantly higher bacterial burden after challenge with L. monocytogenes expressing GP33 compared with the non-irradiated controls, likely due to radiation-induced numerical and functional impairments. Taken together, our findings suggest that sublethal radiation-exposure caused long-term numerical decline, impaired differentiation, and functional dysregulation in pre-existing T CIRCM, which rendered previously-protected hosts susceptible to re-infections. Supported by NIH Grants GM134880, AI114543, The Holden Comprehensive Cancer Center at The University of Iowa and its National Cancer Institute Award P30CA086862