Induction of degenerative brain lesions after adoptive transfer of brain lymphocytes from Borna disease virus-infected rats: presence of CD8+ T cells and perforin mRNA

Abstract

Lymphocytes were isolated from the brains of Borna disease virus-infected donor Lewis rats at various time points after infection. Cell populations were characterized by cytofluorometry, with special emphasis on CD4+ and CD8+ cells. Testing of isolated lymphocytes revealed major histocompatibility complex class I-restricted cytotoxic activity. Reverse transcription-PCR analyses of brain homogenates of infected donors revealed the presence of CD8 mRNA after day 11 of infection and of perforin mRNA between days 13 and 25 after infection. Adoptive transfers of lymphocytes isolated from the brain at days 13 and 21 resulted in severe neurological symptoms, resembling experimental Borna disease. The onset of disease was dependent on the cell numbers transferred and was clearly related to the appearance of T cells in the brain. CD8+ T cells were found in the parenchyma, whereas CD4+ T cells were found predominantly in perivascular locations. A disseminated lymphocytic infiltration in the parenchyma was accompanied by severe morphological alterations, including significant necrosis of neurons. Furthermore, a prominent spongiform-like degeneration was observed; this increased over time and finally resulted in severe cortical brain atrophy. Lymphocytes obtained during the beginning chronic phase of experimental Borna disease in rats had no significant cytolytic capacity in vitro and were also not able to induce neurological symptoms typical of Borna disease after adoptive transfer. The data presented here show for the first time that lymphocytes isolated from the site of the inflammatory lesions, namely, the brains of diseased rats, induce the immunopathological reaction and cause Borna disease. After transfer, the pathological alterations induced in the recipients exactly reflect those observed during experimentally induced Borna disease in rats, including necrosis of neurons and glial cells and gross degeneration resulting in cortical brain atrophy. Evidence that the immunopathology of Borna disease is closely related to the presence of CD8+ T cells in the brain parenchyma is provided.