The Neuroimmune Duality of CD4⁺ T Cells: Drivers of Damage and Repair in the Brain.

CD4⁺ T cells are central regulators of neuroimmune responses, and their dysregulation is increasingly recognized as a pathogenic driver across multiple neurological disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), ischemic stroke (IS), traumatic brain injury (TBI), central nervous system (CNS) infections, and stress-induced vestibular dysfunction. This review outlines the differentiation and functional specialization of CD4⁺ T cell subsets T helper 1 (Th1), Th17, Th2, Th9, regulatory T cells (Tregs), and T follicular helper (Tfh) cells and evaluates their distinct roles in CNS injury and repair. In MS, autoreactive Th17 cells promote demyelination through C-C chemokine receptor type 6 (CCR6)-C-C motif ligand 20 (CCL20)-mediated CNS trafficking and granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent microglial activation. In contrast, neurodegenerative conditions involve antigen-specific CD4⁺ T cell responses to disease-associated neoantigens, including amyloid-beta (Aβ) and tau in AD, and α-synuclein in PD, often preceding clinical manifestation. Disease-specific differences in antigen identity, glial crosstalk, and temporal infiltration patterns are described for each condition. Age-related CD4⁺ T cell dysfunction, encompassing thymic involution, imbalance between naïve and memory T cell populations, diminished plasticity, and metabolic alterations in senescent lymphocytes, is discussed as a contributor to chronic neuroinflammation in aging. Current and emerging therapeutic strategies are evaluated, including disease-modifying therapies, immune checkpoint modulation, cytokine blockade, Treg-based adoptive transfer, antigen-specific tolerance via nanoparticle systems, metabolic interventions, and chimeric antigen receptor (CAR)-Treg and gene-based approaches. Collectively, these insights indicate the importance of CD4⁺ T cell dynamics in shaping targeted immunotherapeutic strategies for neurological diseases.