CD8+ lymphocyte-mediated injury of dorsal root ganglion neurons during lentivirus infection: CD154-dependent cell contact neurotoxicity.
Neuronal damage in dorsal root ganglia (DRGs) with accompanying axonal injury is a key feature of human immunodeficiency virus (HIV)-related distal sensory polyneuropathy (DSP). In a model of HIV-related DSP, we observed numerous CD3+ T lymphocytes (p < 0.05) in DRGs from feline immunodeficiency virus (FIV)-infected animals, which also exhibited low CD4+ and high CD8+ lymphocyte levels in blood accompanied by a selective loss of small-diameter sural nerve axons (p < 0.05). FIV-infected lymphocytes cocultured with syngeneic DRGs caused neuronal damage, indicated by neurite retraction, neuronal soma atrophy, and loss (p < 0.05). In contrast, supernatants from FIV-infected or uninfected lymphocytes were minimally neurotoxic, despite high FIV virion levels. Among lymphocyte subsets cocultured with DRG cultures, CD8+ T cells from both FIV-infected and uninfected lymphocytes selectively caused DRG neuronal injury (p < 0.05). FIV-infected CD8+ T cells showed markedly increased CD154 expression (p < 0.05), whereas neurons were the predominant cells expressing CD40 in DRGs. Blocking CD154 on activated CD8+ T cells protected DRG neurons (p < 0.05). These findings indicated that CD8+ T cells were principal effectors of DRG neuronal injury after FIV infection through a CD40-CD154 interaction in a cell contact-dependent manner.
Department of Medicine, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
Yu
Y
Zhu
Joseph
J
Antony
Shuhong
S
Liu
Jose A
JA
Martinez
Fabrizio
F
Giuliani
Douglas
D
Zochodne
Christopher
C
Power
D000818:Animals; D023201:CD40 Ligand / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D002415:Cats; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016181:Feline Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000473:pathology*; D005727:Ganglia, Spinal / Q000276:immunology / Q000473:pathology; D006801:Humans; D016089:Immunodeficiency Virus, Feline; D010523:Peripheral Nervous System Diseases / Q000276:immunology / Q000473:pathology; D011115:Polyneuropathies / Q000276:immunology / Q000473:pathology; D020671:Posterior Horn Cells / Q000276:immunology* / Q000473:pathology*
D023201:CD40 Ligand