Low‐Dose Interleukin‐2 Reverses Traumatic Brain Injury‐Induced Cognitive Deficit and Pain

Objective Despite the high prevalence, mild traumatic brain injury (mTBI)‐induced chronic headache and cognitive deficits are poorly understood and lack effective treatments. Low‐dose interleukin‐2 (LD‐IL‐2) treatment soon after mTBI or overexpressing IL‐2 in brain astrocytes prior to injury protects mice from developing post‐traumatic headache (PTH)‐related behaviors and cognitive decline. The present study addresses a clinically relevant knowledge gap: whether LD‐IL‐2 treatment long after the initial injury is still effective for chronic PTH and cognitive deficits. Methods mTBI was induced by a noninvasive closed‐head weight drop method. LD‐IL‐2 was administered 4–6 weeks post‐mTBI to assess its effects on chronic PTH‐related facial mechanical hypersensitivity as well as mTBI‐induced impairment in novel object recognition and object location tests. Endogenous regulatory T (Treg) cells were depleted to investigate the mechanism of action of LD‐IL‐2. Results Delayed LD‐IL‐2 treatment abolished chronic PTH‐related behaviors. It also completely reversed mTBI‐induced cognitive impairment in both male and female mice. Treg cell depletion not only prolonged PTH‐related behaviors but also abolished the effects of LD‐IL‐2. Interestingly, LD‐IL‐2 treatment significantly increased the number of Treg cells in dura but not in brain tissues. Interpretation These results suggest that the beneficial effects of LD‐IL‐2 treatment are mediated through the expansion of meningeal Treg cells. Collectively, our study identifies Treg as a cellular target and LD‐IL‐2 as a promising therapy for both chronic PTH and mTBI‐induced cognitive impairment for both males and females, with a wide therapeutic time window and the potential of reducing polypharmacy in mTBI treatment. ANN NEUROL 2024;96:508–525