CD8 T-cell clones dominate brain infiltrates in Rasmussen encephalitis and persist in the periphery

Rasmussen encephalitis (RE) is a rare neurological disorder of childhood characterized by uni-hemispheric inflammation, progressive neurological deficits and intractable focal epilepsy. Destruction of neurons and astrocytes by cytotoxic CD8 T cells has been proposed as a pathogenic mechanism underlying this enigmatic disorder. We tested this hypothesis by analysing the clonal composition and T-cell receptor (TCR) repertoire of CD4 and CD8 T cells using complementarity determining region 3 (CDR3) spectratyping from peripheral blood and corresponding CNS specimens. Severe perturbations of the TCR repertoire were found in brain infiltrates from all specimens (n 5). Clonal expansions, as evidenced by peripheral blood analysis (n 14), belonged to the CD8 T-cell subset, while CD4 cells showed normal distributions. Some of those expansions were analysed in the respective CNS specimens by histochemistry. The stainings showed V specific T cells containing the cytotoxic molecule granzyme B and lying in close appositions to NeuN neurons and GFAP astrocytes. Analysis of corresponding CNS/blood specimens revealed overlapping but also CNS-restricted expansions of certain TCR clonotypes suggesting expansions of T cells within the target organ itself. Longitudinal analysis of peripheral blood samples (n 5) demonstrated dominance but also longitudinal persistence of specific CD8 T-cell clones over time. The V/J usage, length of the CDR3, and biochemical characteristics of the CDR3 amino acids suggested high similarities putatively related to common driving antigen(s) without shared clones. Taken together, our data strongly support the hypothesis of an antigen-driven MHC class-I restricted, CD8 T cell-mediated attack against neurons and astrocytes in the CNS dominating the pathogenesis in RE.