Delineating the short- and long-term impact of ionizing radiation on antigen-inexperienced CD8⁺ T cell subsets

Radiation-induced lymphopenia (RIL) remains a challenging side effect of radiation therapy that is often associated with poor prognosis and reduced overall survival. Although CD8⁺ T cells are highly radiosensitive, the dynamics of quantitative and qualitative changes to the CD8⁺ T cell pool following exposure to high doses of ionizing radiation (IR) remain understudied. Herein, we sought to determine the long-term impact of sublethal whole body irradiation (WBI) on the antigen-inexperienced (Ag-inexperienced) CD8⁺ T cell pool, comprising naive (T_N) and virtual memory (T_VM) CD8⁺ T cells. We show that although both T_N and T_VM cells gradually regenerated after WBI-induced loss, T_N recovery occurred only through de novo thymic production. Despite the numerical restoration, the subset and phenotypic composition of postrecovery Ag-inexperienced CD8⁺ T cells did not qualitatively recapitulate the pre-WBI state. Specifically, the frequency of T_VM cells is increased, especially during the early stages of recovery. Within the T_N subset, a lasting overrepresentation of Ly6C⁺CD122⁺ cells and an altered TCR clonotype diversity are also observed. Overall, our data highlight the dynamic changes to the Ag-inexperienced CD8⁺ T cell pool upon recovery from RIL.