Impact of innate immune activation on T cell dynamics and functional recovery following traumatic brain injury

Traumatic brain injury (TBI) initiates a rapidly evolving and temporally ordered neuroinflammatory response; however, it remains unclear whether early interleukin-1β (IL-1β)-producing myeloid cells instruct the subacute T cell response, and whether targeting them improves functional recovery. Here, we tested whether neutrophils, CCR2-dependent monocytes, or NLRP3 inflammasome-dependent IL-1β are required for post-traumatic T cell effector programming and functional outcome. Using a controlled cortical impact model in adult male C57BL/6J mice, we investigated whether targeting key innate inflammatory compartments influenced subsequent adaptive immune programming and neurological outcomes. We conducted longitudinal immune profiling by multiparameter spectral flow cytometry, qPCR and histological assessments up to 28 days post-injury. Antibody-based immune depletion strategies were used to investigate neutrophil and monocyte contributions to the post-traumatic adaptive immune response, while pharmacological inhibition of NLRP3 inflammasome by MCC950 treatment was used to investigate the contribution of IL-1β. TBI elicited a structured early innate immune response, marked by rapid chemokine induction, followed by temporally distinct infiltration of neutrophils, monocytes, and dendritic cells. Neutrophils and monocytes were the predominant early IL-1β-producing infiltrating populations. This was followed by a delayed adaptive phase characterized by sustained recruitment of T cell subsets (CD4 + , CD8 + , γδ), alongside dynamic effector cytokine production (IL-17, IFN-γ). Neutrophil depletion altered the early myeloid composition but did not result in durable improvements in T cell effector responses or neurobehavioral outcomes. Depletion of CCR2-dependent inflammatory monocytes reduced acute monocyte accumulation and attenuated early downstream T cell responses; however, these effects were not sustained, and resulted in modest, assay dependent neurobehavioural benefits. In contrast, inhibition of the NLRP3 inflammasome reduced the number of IL-1β + microglia, without significantly altering leukocyte recruitment or subacute T cell effector phenotypes. NLRP3 inflammasome inhibitor improved motor and cognitive neurobehavioural outcomes but did not reduce TBI lesion volume or perilesional microglial or astrocyte reactivity. Our data demonstrate that CCR2-dependent monocytes shape the acute T cell response after TBI, but T cell suppression was neither sustained nor sufficient for functional recovery, whereas NLRP3 inflammasome inhibition suppressed IL-1β + microglia and improved neurobehavioral outcomes without altering T cell responses or structural changes in the injured brain. These findings define a candidate IL-1β-linked myeloid–T cell axis and show that behavioural benefit after TBI can dissociate from immune cell abundance, indicating that cellular compensation warrants consideration in future immunotherapeutic design.