The immunological paradox of CD4⁺ T cells in traumatic brain injury

Traumatic brain injury (TBI) initiates a prolonged and complex immune response that critically shapes both secondary injury and long-term recovery. Among adaptive immune cells, CD4⁺ T cells have emerged as central regulators of neuroinflammatory processes, acting as a double-edged sword that can be either neuroprotective or neurotoxic. This review focuses on the roles of major CD4⁺ T cell subsets - Th1, Th2, Th17, and regulatory T cells (Tregs) - in modulating the immune landscape following TBI, with an emphasis on their temporal dynamics, phenotypic plasticity, and therapeutic potential. We examine how blood-brain barrier disruption and innate immune activation facilitate T cell infiltration into the central nervous system and outline the cytokine networks and signaling pathways that orchestrate CD4⁺ T cell differentiation and functional polarization. Advances in single-cell RNA sequencing (scRNA-seq) have provided new insights into the transcriptional heterogeneity of CD4⁺ T cells post-TBI, offering novel angles for therapeutic targeting. In addition, we assess current strategies for targeting CD4⁺ T cells therapeutically and examine translational challenges, particularly the translational gap between animal models and human disease. To provide a focused synthesis, this review does not delve into all immune cell types or other aspects of neuroinflammation that may also play significant roles in TBI.