Natural killer T cells as therapeutic targets for neuroinflammatory disorders

Natural killer T (NKT) cells are innate-like T lymphocytes that express natural killer (NK) cell receptors (NKRs), which recognize glycolipid antigens presented by the MHC class I-like protein CD1d, linking innate and adaptive immunity. NKT cells include two main subsets, type I and type II, which differ in TCR usage and antigen specificity. In addition, NKT-like cells, which express NKRs but are CD1d-independent, have attracted growing interest in neuroimmunology. These NKR-expressing T cells play important roles in either promoting or suppressing pathological conditions within the brain. This review overviews recent advances in understanding NKT cells in immune disorders of the central nervous system (CNS), including neurodegenerative diseases, neuroinflammation, autoimmune diseases, brain injury, and CNS malignancies, such as glioblastoma. By interacting with CD1d on non-immune cells (e.g. astrocytes) and immune cells (e.g. microglia) through their TCR, type I NKT cells help maintain or disrupt immune homeostasis in the CNS. In addition, exogenous ligands, such as alpha-galactosylceramide, can modify type I and type II NKT cell phenotypes and promote regulatory functions in NKT-like cells, which may mitigate excessive inflammation. This review provides insights into how NKT cell subsets could serve as therapeutic targets for neuroinflammatory diseases.