Activated CD8+ T Cells Cause Long-Term Neurological Impairment after Traumatic Brain Injury in Mice
Maria Daglas,
Dominik F. Draxler,
Heidi Ho,
Fiona McCutcheon,
Adam Galle,
Amanda E. Au,
Pia Larsson,
Julia Gregory,
Frank Alderuccio,
Maithili Sashindranath,
Robert L. Medcalf
Affiliations
Maria Daglas
Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
Dominik F. Draxler
Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
Heidi Ho
Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
Fiona McCutcheon
Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
Adam Galle
Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
Amanda E. Au
Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
Pia Larsson
Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
Julia Gregory
Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
Frank Alderuccio
Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
Maithili Sashindranath
Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; Corresponding author
Robert L. Medcalf
Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; Corresponding author
Summary: Traumatic brain injury (TBI) leaves many survivors with long-term disabilities. A prolonged immune response in the brain may cause neurodegeneration, resulting in chronic neurological disturbances. In this study, using a TBI mouse model, we correlate changes in the local immune response with neurodegeneration/neurological dysfunction over an 8-month period. Flow cytometric analysis reveals a protracted increase in effector/memory CD8+ T cells (expressing granzyme B) in the injured brain. This precedes interleukin-17+CD4+ T cell infiltration and is associated with progressive neurological/motor impairment, increased circulating brain-specific autoantibodies, and myelin-related pathology. Genetic deficiency or pharmacological depletion of CD8+ T cells, but not depletion of CD4+ T cells, improves neurological outcomes and produces a neuroprotective Th2/Th17 immunological shift, indicating a persistent detrimental role for cytotoxic T cells post-TBI. B cell deficiency results in severe neurological dysfunction and a heightened immune reaction. Targeting these adaptive immune cells offers a promising approach to improve recovery following TBI. : Daglas et al. show that granzyme B+CD8+ T cells accumulate in the brain after traumatic brain injury, triggering chronic neurological/motor impairment and myelin pathology. Genetic deficiency/pharmacological depletion of CD8+ T cells, but not B cells, promotes recovery post-injury and offers a therapeutic option to minimize long-term disabilities in trauma patients. Keywords: traumatic brain injury, CD8+ T cells, adaptive immune cells, B cells, autoantibodies, neuroimmunology, granzyme B
