Chronic traumatic brain injury induces neurodegeneration, neuroinflammation, and cognitive deficits in a T cell-dependent manner

Leyre Ayerra; Kirill Shumilov; Allen Ni; Maria S Aymerich; Stuart H Friess; Marta Celorrio

doi:10.1016/j.brainres.2025.149446

Chronic traumatic brain injury induces neurodegeneration, neuroinflammation, and cognitive deficits in a T cell-dependent manner

Brain Res. 2025 Jan 10:149446. doi: 10.1016/j.brainres.2025.149446. Online ahead of print.

Authors

Leyre Ayerra¹, Kirill Shumilov², Allen Ni³, Maria S Aymerich¹, Stuart H Friess³, Marta Celorrio⁴

Affiliations

¹ Department of Biochemistry and Genetics, University of Navarre, Pamplona, Spain; Gene Therapy for Neurological Diseases, CIMA-University of Navarre, Pamplona, Spain.
² Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, USA.
³ Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
⁴ Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, USA. Electronic address: m.c.narvarro@wustl.edu.

PMID: 39800094
DOI: 10.1016/j.brainres.2025.149446

Abstract

Traumatic brain injury (TBI) can lead to chronic neuroinflammation, and neurodegeneration associated with long-term cognitive deficits. Following TBI, the acute neuroinflammatory response involves microglial activation and the release of proinflammatory cytokines and chemokines which induce the recruitment of peripheral immune cells such as monocytes and ultimately T cells. Persistent innate and adaptive immune cells response can lead to chronic neurodegeneration and functional deficits. Therefore, understanding the dynamic interaction between chronic immune responses and TBI-related pathogenesis and progression of the disease is crucial. We hypothesized that T cells have an essential role in TBI severity and recovery. We used generic T cell deletion mice (TCRβ^-/-δ^-/-) vs Wild-type mice that underwent to controlled cortical impact assessing behavioral, histological, and immune system response outcomes at 3 months post-TBI. The absence of T cells reduced neurodegeneration and was associated with improved neurological outcomes 3 months post-injury. Furthermore, the absence of T cells enhanced an anti-inflammatory phenotype in peripheral myeloid cells in the injured brain. Collectively, these data indicate that T cells promote persistent neuropathology and functional impairments chronically after TBI.

Keywords: And fear memory; Monocytes; Neurodegeneration; T cells; Traumatic brain injury.