Type 1 lymphocytes and interferon-γ accumulate in the thalamus and restrict seizure susceptibility after traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of mortality and disability worldwide and can lead to secondary sequelae such as increased seizure susceptibility. Emerging work suggests that the thalamus, the relay center of the brain that undergoes secondary damage after cortical TBI, is involved with heightened seizure risks after TBI. TBI also induces the recruitment of peripheral immune cells, including T cells, to the site(s) of injury, but it is unclear how these cells impact neurological sequelae post-TBI. Here, we characterize the identities and kinetics of lymphocytic infiltrates into the cortex and thalamus using a mouse model of cortical TBI. We identify a population of IFNγ-producing type 1 lymphocytes that infiltrate specific thalamic subregions over weeks following injury, where they elicit a local IFNγ response in microglia and neuronal subset(s). Depletion of CD4 T cells protects mice from TBI-induced seizure susceptibility by de-repressing other non-CD4 type 1 lymphocytes and disease-associated microglia (DAMs) in the thalamus. Strikingly, we find that a single dose of IFNγ prior to challenge with a proconvulsant agent was sufficient to reduce TBI-induced seizure incidence, severity, and mortality. This work identifies IFNγ as a direct modulator of TBI-associated seizure susceptibility, which could have therapeutic implications for the treatment of TBI patients.