Radiation causes long term changes in virus-specific and virtual memory CD4 T cells

Abstract Threat of nuclear attack and accidents at nuclear power plants increase our risk of radiation exposure. Radiation effects on immune homeostasis are well-studied, but their effect on memory CD4 T cells is poorly defined. To explore that, we adoptively transferred naïve Thy1.1 TCR-Tg SMARTA CD4 T cells specific for LCMV-derived gp61 epitope into naïve Thy1.2 C57BL/6 mice before LCMV-Armstrong infection. At memory time point, infected recipient mice were subjected to 0Gy (non-radiated, control group) or 5Gy of total body radiation. We found that naïve CD4 T cells suffered significant numerical loss post radiation, but they numerically recovered in few weeks through increased proliferative expansion. However, radiated SMARTA and endogenous GP61-specific memory CD4 T cells sustained a prolonged loss in number that fail to recover even after 3 months. Radiation also leads to transient impairment in the ability of memory CD4 T cells to produce cytokines (IFNγ, TNFα) in response to cognate antigen stimulation, or to proliferate upon adoptive transfer into new hosts in response to secondary LCMV infection. Interestingly, the endogenous ‘effector-like’ CD4 T cell numbers recovered faster than SMARTA memory T cells. We hypothesized that virtual memory T cells (CD4 Tvm) are contributing to the recovery of this effector like CD4 T cells in the radiation mediated lymphoreplete conditions. Tetramer enrichment of CD4 T cells specific to the gp66 and 2W1S epitope showed that radiation increases the representation of gp66 specific CD4 Tvm in naïve mice. Together, these data suggest that radiation poses long-lasting defects to virus specific memory CD4 T cell responses, and it facilitates CD4 Tvm proliferation to overcome the lymphopenia.