Whole-body irradiation causes long-term impairments in the maintenance and function of naïve CD4 T cells specific for self- and non-self-antigens.

Whole-body irradiation (WBI) consistently induces radiation-associated lymphopenia, a complication linked to poor prognosis and reduced overall survival. Understanding the quantitative and qualitative changes in naïve CD4 T cells after WBI is critical because these cells play key roles in both host defense and the propagation of autoimmunity. Here, we show that WBI triggers a rapid decline in the naïve CD4 T-cell pool, followed by thymus-dependent numerical recovery. Shortly after WBI, mice exhibit a reduced frequency of lymphocytic choriomeningitis virus (LCMV) epitope GP66-77-specific naïve CD4 T-cell precursors. Upon infection with LCMV, this reduction leads to delayed effector expansion, impaired memory differentiation, and diminished cytokine production. WBI also disrupts blood-brain barrier (BBB) integrity, enhancing infiltration of GP66-77-specific memory CD4 T cells into the brain and promoting enrichment of brain-resident tissue-resident memory CD4 T cells. Similarly, encephalitogenic MOG38-49-specific CD4 T-cell precursors are reduced after WBI, resulting in delayed but exacerbated experimental autoimmune encephalomyelitis (EAE) compared with nonirradiated controls. WBI-mediated BBB disruption facilitates the entry of encephalitogenic MOG38-49-specific CD4 T cells into the spinal cord, promoting EAE induction and progression even in the absence of pertussis toxin administration. Together, these findings highlight both immune-intrinsic and -extrinsic effects of WBI in shaping naïve CD4 T-cell responses in the context of infection and autoimmunity.