T-cell infiltration is associated with increased reactive astrocytosis and tumor necrosis factor alpha in intraventricular hemorrhage

Intraventricular hemorrhage (IVH), the most common, severe neurological complication of preterm birth, causes post-hemorrhagic hydrocephalus (PHH) in up to 30% of cases, which is associated with substantial morbidity. IVH/PHH pathophysiology is multifactorial, involving impaired cerebrospinal fluid (CSF) circulation and/or absorption, and periventricular white matter and ventricular zone alterations. While neuroinflammation has been implicated in its pathophysiology, the role of T cells remains undetermined. Post-natal day 4 wild-type (WT) and TCRβ-/-δ-/- knockout (TCR KO) mice of both sexes received intraventricular injections of either 5 μl lysed blood (IVH) or artificial CSF (sham). Seven days post-induction, magnetic resonance imaging (MRI) was performed to quantify ventricular volume. Brains and blood samples were collected for histology, immunofluorescence, and spectral flow cytometry. Neonatal WT IVH/PHH was associated with ventriculomegaly, and significant increases in T-cell infiltration, GFAP + vimentin + astrocytes and tumor necrosis factor alpha (TNF-α) in the periventricular white matter. TCR depletion prevented reactive gliosis and decreased TNF-α levels in the periventricular white matter of TCR KO IVH mice compared to TCR KO sham. When T cells were depleted, no significant changes were observed in the number of iba1 + microglia/macrophages in the periventricular white matter, extent of ventricular zone disruption, and ventricular size. These findings link T cells, astrocyte reactivity, and TNF-α levels in IVH/PHH pathophysiology and support the notion of targeted immunotherapy to treat or prevent IVH/PHH-related periventricular white matter pathology.