Virus-specific memory CD4 T cells sustain long-term numerical and functional impairment following whole-body irradiation

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The increasing demand for nuclear power and radiotherapy has expanded potential avenues for human exposure to whole-body irradiation (WBI), underscoring the need to understand its impact on immune cells. While prior studies have explored radiation-induced disruptions in immune homeostasis, the direct effect of WBI on pre-existing memory CD4 T cells remains elusive. Using T cell receptor transgenic CD4 T cell chimeric mice infected with lymphocytic choriomeningitis virus-Armstrong, we demonstrate that a sublethal WBI dose (5 Gy) causes a significant and persistent reduction in the numbers of memory CD4 T cells for at least 30 d post-WBI. At 8 d post-WBI, memory CD4 T cells exhibited an increased frequency of Ly6C+ T helper 1 cells and a decreased frequency of PSGL1+Ly6C- central memory cells in the spleen compared with mock-irradiated (0 Gy) control mice. These subset imbalances were no longer detectable by 30 d post-WBI. However, surviving memory CD4 T cells exhibited intrinsic functional impairments, including reduced production of the proinflammatory cytokines IFNγ, TNFα, and IL-2 upon ex vivo stimulation with the gp61-80 peptide. Furthermore, irradiated T cell receptor transgenic memory CD4 T cells exhibited defective secondary expansion upon pathogen re-encounter in unmanipulated hosts. Finally, the irradiated primary memory CD4 T cells exhibited poor protection potential, as they were unable to clear the pathogen upon re-exposure as effectively as their 0 Gy counterpart. In summary, sublethal WBI impairs the kinetics, subset composition, and function of memory CD4 T cells, ultimately compromising their ability to mount effective recall responses to clear the infection.