The functional avidity of virus-specific CD8+ T cells is downmodulated in Borna disease virus-induced immunopathology of the central nervous system

Borna disease virus (BDV) infection of the central nervous system (CNS) leads to severe neurological symptoms in susceptible MRL mice. The disease is mainly mediated by CD8(+) T cells specific for the immunodominant epitope TELEISSI in the BDV nucleoprotein. In this study, TELEISSI/MHC class I tetramers were used to directly visualize antigen-specific CD8(+) T cells. We found that on average approximately 30% of the ex vivo analyzed CD8(+) T cells in the CNS of diseased mice were specific for TELEISSI. Unexpectedly, the frequency of tetramer-reactive brain-derived CD8(+) T cells doubled following overnight culture in the absence of antigen. The majority of CD8(+) T cells showed enhanced tetramer binding without up-regulation of T cell receptor surface expression. The frequency of IFN-gamma-secreting CD8(+) T cells after antigen-specific stimulation was higher in overnight cultures than in freshly isolated BDV-specific brain lymphocytes, and enhanced tetramer binding correlated with elevated sensitivity to lower levels of peptide antigen in cytotoxicity assays. These results indicate that the functional avidity of virus-specific CD8(+) T cells was down-modulated in vivo. Thus, quantification of tissue-infiltrating CD8(+) T cells by the tetramer technique must be interpreted with caution as it may underestimate the real frequency of antigen-specific CD8(+) T cells.