title: Therapeutic antiviral T cells noncytopathically clear persistently infected microglia after conversion into antigen-presenting cells.
abstract: Several viruses can infect the mammalian nervous system and induce neurological dysfunction. Adoptive immunotherapy is an approach that involves administration of antiviral T cells and has shown promise in clinical studies for the treatment of peripheral virus infections in humans such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus, among others. In contrast, clearance of neurotropic infections is particularly challenging because the central nervous system (CNS) is relatively intolerant of immunopathological reactions. Therefore, it is essential to develop and mechanistically understand therapies that noncytopathically eradicate pathogens from the CNS. Here, we used mice persistently infected from birth with lymphocytic choriomeningitis virus (LCMV) to demonstrate that therapeutic antiviral T cells can completely purge the persistently infected brain without causing blood-brain barrier breakdown or tissue damage. Mechanistically, this is accomplished through a tailored release of chemoattractants that recruit antiviral T cells, but few pathogenic innate immune cells such as neutrophils and inflammatory monocytes. Upon arrival, T cells enlisted the support of nearly all brain-resident myeloid cells (microglia) by inducing proliferation and converting them into CD11c(+) antigen-presenting cells (APCs). Two-photon imaging experiments revealed that antiviral CD8(+) and CD4(+) T cells interacted directly with CD11c(+) microglia and induced STAT1 signaling but did not initiate programmed cell death. We propose that noncytopathic CNS viral clearance can be achieved by therapeutic antiviral T cells reliant on restricted chemoattractant production and interactions with apoptosis-resistant microglia.
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Herz
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Kory R
authors.initials: KR
authors.lastname: Johnson
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892 mcgavernd@mail.nih.gov.
authors.forename: Dorian B
authors.initials: DB
authors.lastname: McGavern
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D039521:CD11c Antigen / Q000378:metabolism; D005070:Evans Blue; D005434:Flow Cytometry; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000628:therapy*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D017628:Microglia / Q000821:virology*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*
chemical_list: D039521:CD11c Antigen; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D005070:Evans Blue