CD4+ CD11b+ T cells infiltrate and aggravate the traumatic brain injury depending on brain-to-cervical lymph node signaling

Abstract

Aim: We aim to identify the specific CD4⁺ T-cell subtype influenced by brain-to-CLN signaling and explore their role during the acute phase of traumatic brain injury (TBI).

Method: Cervical lymphadenectomy or cervical afferent lymphatic ligation was performed before TBI. Cytokine array and western blot were used to detect cytokines, while the motor function was assessed using mNss and rotarod test. CD4⁺ T-cell subtypes in blood, brain, and CLNs were analyzed with Cytometry by time-of-flight analysis (CyTOF) or fluorescence-activated cell sorting (FACS). Brain edema and volume changes were measured by 9.4T MRI. Neuronal apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining.

Results: Cervical lymphadenectomy and ligation of cervical lymphatic vessels resulted in a decreased infiltration of CD4⁺ T cells, specifically CD11b-positive CD4⁺ T cells, within the affected region. The population of CD4⁺ CD11b⁺ T cells increased in ligated CLNs, accompanied by a decrease in the average fluorescence intensity of sphingosine-1-phosphate receptor-1 (S1PR1) on these cells. Administration of CD4⁺ CD11b⁺ T cells sorted from CLNs into the lateral ventricle reversed the attenuated neurologic deficits, brain edema, and lesion volume following cervical lymphadenectomy.

Conclusion: The infiltration of CD4⁺ CD11b⁺ T cells exacerbates secondary brain damage in TBI, and this process is modulated by brain-to-CLN signaling.

Keywords: CD4+ T cell; brain-to-cervical lymph node signaling; immunoregulation; traumatic brain injury.