Therapeutic clearance of the virally infected nervous system is mediated by noncytopathic T cell interactions with resident myeloid cells (P4220)

Abstract

Abstract Several viruses can infect the mammalian nervous system, some with devastating consequences, and others with little or no overt pathology. Adoptive immunotherapy is an approach that has shown promise in clinical studies for the treatment of CMV, EBV and adenovirus infections. Our laboratory models immunotherapy by transferring memory T cells into mice persistently infected from birth with lymphocytic choriomeningitis virus. Here, we demonstrate that memory T cells can completely purge the brain of persistently infected mice without causing blood brain barrier breakdown or severe tissue damage. This is accomplished by a tailored release of chemoattractants that recruit adaptive immune cells, but few pathogenic innate immune cells such as neutrophils and inflammatory monocytes. Interestingly, memory T cells enlist the support of nearly all brain resident myeloid cells (microglia) by converting them into CD11c-expressing antigen-presenting cells (APC). Two-photon imaging studies revealed that anti-viral CD8 T cells are more likely to decelerate and form stable interactions with brain-resident APC than CD4 T cells. Importantly, microglia do not undergo cell death following T cell engagement and appear to protect themselves by upregulating serine protease inhibitors like Spi-6. We propose that non-cytopathic viral clearance from the brain by therapeutic memory T cells results from tailored chemoattractant production and interactions with resident myeloid cells protected by Spi-6.