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

Abstract

Abstract 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.