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

Threja, S.; Strogulski, N.; Laabei, J.; Vegliante, G.; Douglas, C.; Bogale, T. A.; Moynihan, C.; Di Franco, G.; Mack, M.; Borkner, L.; Diallo, B.; Mills, K.; Loane, D.

doi:10.64898/2026.03.23.713833

bioRxiv · 10.64898/2026.03.23.713833

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

Threja, S.·Strogulski, N.·Laabei, J.·Vegliante, G.·Douglas, C.·Bogale, T. A.·Moynihan, C.·Di Franco, G.·Mack, M.·Borkner, L.·Diallo, B.·Mills, K.·Loane, D.

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Abstract

BackgroundTraumatic brain injury (TBI) initiates a rapidly evolving neuroinflammatory response; however, the temporal relationship between early innate immune activation, T cell polarization, and neurobehavioural recovery remains poorly understood. Here, we hypothesize that interleukin-1{beta} (IL-1{beta}) is a critical upstream mediator that polarizes T cells towards pro-inflammatory and cytotoxic effector functions following TBI. MethodsUsing a controlled cortical impact model in adult male C57BL/6J mice, we mapped post-injury immune dynamics and investigated whether targeting key innate inflammatory compartments influenced subsequent T cell programming and neurological outcomes. We conducted longitudinal immune profiling by multiparameter spectral flow cytometry and quantitative polymerase chain reaction up to 10 days post-injury. Antibody-based immune depletion strategies were used to investigate neutrophil and monocyte contributions to the post-traumatic T cell response, while pharmacological inhibition of NLRP3 inflammasome by MCC950 treatment was used to investigate the contribution of IL-1{beta}. ResultsTBI 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-1{beta}-producing infiltrating populations. This was followed by a delayed adaptive phase characterized by sustained recruitment of T cell subsets (CD4+, CD8+, {gamma}{delta}+), alongside dynamic effector cytokine production (IL-17, IFN-{gamma}). 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 only resulted in modest neurobehavioural benefits. In contrast, inhibition of the NLRP3 inflammasome suppressed microglial IL-1{beta} production, without significantly altering leukocyte recruitment or subacute T cell effector phenotypes. These phenotypic changes were associated with improvements in motor and cognitive function recovery. ConclusionWe show that early monocyte IL-1{beta} signalling actively regulates downstream T cell infiltration and effector function after TBI. In addition, inhibition of NLRP3 inflammasome after TBI attenuates microglial IL-1{beta}-associated immune activation and results in behavioural improvement despite ongoing leukocyte recruitment, indicating that targeting the nature and cellular source of IL-1{beta} signalling can dissociate immune cell burden from neurological outcomes. Collectively, our findings identify myeloid IL-1{beta}-linked pathways as a viable bridge between innate and adaptive immunity post-TBI, and underscore cellular compensation as a critical design consideration for next-generation immunotherapies.

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Threja, S., Strogulski, N., Laabei, J., Vegliante, G., Douglas, C., Bogale, T. A., Moynihan, C., Di Franco, G., Mack, M., Borkner, L., Diallo, B., Mills, K., Loane, D.. 2026-03-26. Impact of innate immune activation on T cell dynamics and functional recovery following traumatic brain injury. https://doi.org/10.64898/2026.03.23.713833

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