T cells in antibody-associated CNS autoimmunity: a mechanistic approach across autoimmune encephalitis and paraneoplastic disorders

PURPOSE OF REVIEW: Autoimmune encephalitis (AE), paraneoplastic neurological syndromes (PNS), and glial antibody-mediated disorders (for example, AQP4-NMOSD) are traditionally classified based on the target antigens of their respective autoantibodies. However, recent insights from immunogenomics, single-cell sequencing, and neuropathology indicate that T cell programs substantially influence disease initiation, localization, and chronicity. This review highlights three emerging dimensions of T-cell involvement - circulating exhausted-like helper T-cell memory, intrathecal T-B cooperation, and parenchymal tissue-resident cytotoxicity - that offer new perspectives on clinical and pathological features across these disorders. RECENT FINDINGS: In AQP4-NMOSD, circulating exhausted-like CD4 + T cells may constitute a durable autoreactive memory reservoir capable of re-initiating plasmablast responses. In LGI1- and CASPR2-associated encephalitis, systemic and intrathecal CD4 + differentiation appears to support systemic antibody maturation and local plasmablast expansion, with emerging hints of some accompanying CD8 + -mediated tissue injury. In contrast, in PNS and intracellular antigen-associated AE, CD8 + T cell-mediated cytotoxicity dominates and is characterized by parenchymal CD8 + tissue-resident memory (TRM) signatures. SUMMARY: These T-cell dimensions may provide a useful framework for understanding clinical paradoxes - such as relapse despite B-cell depletion, persistent memory dysfunction in IgG4-AE, and therapeutic inefficacy in PNS - and suggest opportunities for therapeutic strategies targeting exhausted T-cell memory, intrathecal cooperation, or TRM stability.