Delineating the short- and long-term impact of ionizing radiation on antigen-inexperienced CD8+ T cell subsets
Mohammad Heidarian, Shravan K. Kannan, Whitney Swanson, Thomas S. Griffith, John T. Harty, Vladimir P. Badovinac
Mohammad Heidarian, Shravan K. Kannan, Whitney Swanson, Thomas S. Griffith, John T. Harty, Vladimir P. Badovinac
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Research Article Immunology Inflammation

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

Abstract

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

Authors

Mohammad Heidarian, Shravan K. Kannan, Whitney Swanson, Thomas S. Griffith, John T. Harty, Vladimir P. Badovinac

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Figure 4

WBI-surviving naive CD8+ T cells exhibit diminished proliferative capacity.

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WBI-surviving naive CD8+ T cells exhibit diminished proliferative capaci...
(A) Experimental design: 106 naive Thy1.1+ P14 CD8+ T cells were adoptively transferred into Thy1.2+ naive hosts followed by exposure to 0 Gy or 5 Gy dose of WBI 2 days later. Spleens were harvested and analyzed at indicated time points. (B) Representative flow plots of P14 CD8+ T cells and endogenous naive (TN) and virtual memory (TVM) CD8+ T cells in 0 Gy and 5 Gy mice at D34 after WBI. (C) Number of endogenous TN cells (left) and P14 cells (right) in 0 Gy and 5 Gy hosts at indicated time points after WBI. (D) Experimental design: 7.5 × 105 naive P14 CD8+ T cells were adoptively transferred to Thy1.2+ naive hosts that had undergone 0 Gy or 5 Gy WBI 2 days prior. Longitudinal blood analysis was performed at indicated time points. (E) Number of endogenous TN cells (left) and naive P14 cells (right) in 0 Gy and 5 Gy hosts at indicated time points after WBI. (F) Frequency of P14 and TN cells that express Ki67 in 0 Gy and 5 Gy hosts at D10 after WBI. Data in A–F are representative of 2 independent experiments with n = 5–8 mice per group in each experiment. Statistical significance was determined by 2-way ANOVA with Bonferroni’s multiple comparisons post hoc test using GraphPad Prism. Graphs show the mean ± SEM with each symbol representing 1 mouse. Individual P values are noted on respective graphs or are summarized as follows: **P < 0.01, ***P < 0.001.