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

Abstract

The increasing use of nuclear energy sources inevitably raises the risk of accidental or deliberate radiation exposure and associated immune dysfunction. 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 CD8 T cell chimeric mice (P14 chimeras) with an lymphocytic choriomeningitis virus (LCMV) infection model, we observed that sublethal (5Gy) whole-body irradiation (WBI) induced a rapid decline in the number of naive (T N ) and P14 circulating memory CD8 T cells (T CIRCM ), with the former being more susceptible to radiation-induced numeric loss. While T N cell numbers rapidly recovered, as previously described, the number of P14 T CIRCM cells remained low at least 9 mo after radiation exposure. Additionally, the remaining P14 T CIRCM in irradiated hosts exhibited an inefficient transition to a central memory (CD62L + ) phenotype compared to nonirradiated P14 chimeras. WBI also resulted in long-lasting T cell intrinsic deficits in memory CD8 T cells, including diminished cytokine and chemokine production along with impaired secondary expansion upon cognate Ag reencounter. Irradiated P14 chimeras displayed significantly higher bacterial burden after challenge with Listeria monocytogenes expressing the LCMV GP 33-41 epitope relative to nonirradiated controls, likely due to radiation-induced numerical and functional impairments. Taken together, our findings suggest that sublethal radiation exposure caused a long-term numerical, impaired differentiation, and functional dysregulation in preexisting T CIRCM , rendering previously protected hosts susceptible to reinfection.