W201 - Imbalance of γδ T and MAIT Cells and Defective αβ TCR Clonality in Poorly-Controlled Epilepsy

Abstract Text: One-third of epilepsy cases are refractory to anti-seizure medications, highlighting the urgent need for novel therapeutic strategies. Mounting evidence has linked blood-brain barrier (BBB) damage and immune cell regulation to epilepsy, but the immune mechanisms underlying treatment resistance remain elusive. We conducted the first immunomics in the blood and brain of poorly-controlled (PC) and well-controlled (WC) epilepsy using single-cell RNA and T-cell receptor (TCR) sequencing of peripheral (n=106) and brain-infiltrating (n=10) immune cells, coupled with plasma proteomics and metabolomics analyses. Our findings revealed striking alterations in T cell subsets: Gamma-delta (γδ) T-cells were enriched in PC patients, while mucosal-associated invariant T (MAIT) cells were reduced in PC patients, suggesting opposing roles of these innate-like T-cell populations in epilepsy. PC patients exhibited reduced alpha beta (αβ) T-cell clonality, correlating with shorter seizure-free intervals and heightened depression risk. Intriguingly, we identified five TCR clusters shared among epilepsy patients all targeting a cytomegalovirus antigen, implicating viral antigens in driving immune dysfunction. Plasma proteomics implicated impaired coagulation and wound healing pathways in PC patients, indicative of persistent BBB disruption. Brain tissue analysis unveiled reduced T cell infiltration in PC patients compared to post-mortem brain tissue from non-epileptic controls. Remarkably, activated and clonally expanded T cells emerge as potential protectors against epilepsy. These discoveries not only redefine epilepsy as an immune-driven disorder but also unveil antigen-specific T cells as a transformative avenue for refractory cases.