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 (TN) and virtual memory (TVM) CD8+ T cells. We show that although both TN and TVM cells gradually regenerated after WBI-induced loss, TN 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 TVM cells is increased, especially during the early stages of recovery. Within the TN 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.