Transection of Major Histocompatibility Complex Class I-Induced Neurites by Cytotoxic T Lymphocytes

Abstract

Damage to neurites with transection of axons and spheroid formation is commonly noted in the central nervous system during viral and autoimmune diseases such as multiple sclerosis, but it remains open whether such changes are caused primarily by immune mechanisms or whether they are secondary to inflammation. The present experiments explored whether neurites can be directly attacked by cytotoxic T lymphocytes (CTLs). Cultured murine neurons induced by interferon-␥ and tetrodotoxin to express major histocompatibility complex class I were pulsed with a dominant peptide of the lymphochoriomeningitis virus envelope glycoprotein (GP33) and then confronted with GP33-specific CD8 ؉ CTLs. Within 3 hours the neurites developed cytoskeleton breaks with adjacent solitary neuritic spheroids, as documented by confocal examination of the cytoskeletal marker ␤-tubulin III. At the same time cytoskeleton staining of the neuronal somata showed no damage. The CTLs selectively attacked neurites and induced segmental membrane disruption 5 to 30 minutes after the establishment of peptide-specific CTL-neurite contact, as directly visualized by live confocal imaging. Thus, major histocompatibility complex class I/peptide-restricted CD8 ؉ T lymphocytes can induce lesions to neurites, which might be responsible for axonal damage during neuroinflammatory diseases. During viral, autoimmune, and neurodegenerative brain processes, major histocompatibility complex (MHC) class I expression is induced on resident cells including neurons, often followed by infiltration of inflammatory cells into the affected brain tissue.

CD8+ Lymphocyte-Mediated Injury of Dorsal Root Ganglion Neurons during Lentivirus Infection: CD154-Dependent Cell Contact Neurotoxicity

“…FIV-infected PBLs, with or without PMA stimulation, were particularly toxic to DRG neurons in terms of retraction of neurite length, neuronal soma atrophy, and loss when cocultured with syngeneic DRGs. These findings are consistent with previous reports that activated T cells could injure neurons in both syngeneic and allogeneic mechanisms in vitro (Manning et al, 1987;Rall et al, 1995;Medana et al, 2001a;Giuliani et al, 2003). HIV infection can also elicit autoreactive T cell responses in the circulation and in the brains of infected hosts (Lin et al, 2005); these findings resembled the marked influx and adverse effects of T cells in DRGs of FIV-infected animals, whereas the few resident T cells in DRGs of healthy cats did not exert deleterious effects on neurons.…”

“…Previous studies show that allogeneic T cells can kill mouse peripheral nervous system neurons (Manning et al, 1987), and antigen (Ag)-specific T cells are toxic to syngeneic mouse neurons on which major histocompatibility complex class I (MHC-I) expression was required (Rall et al, 1995;Medana et al, 2001a). More recent reports have revealed that activated T cells cocultured with human neurons or with mouse brain slices led to substantial neuronal death, regardless of whether the T cells were allogeneically and syngeneically derived (Rall et al, 1995;Medana et al, 2001a;Giuliani et al, 2003;Hannila and Kawaja, 2003). However, some studies have emphasized the point that cytotoxicity was mediated through cell contact-dependent mechanisms in which FasL, perforin, or CD154 and their cognate receptors were involved (Giuliani et al, 2003;Nitsch et al, 2004).…”

Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

“…However, in resistant mouse strains (C57Bl/6), the infection is cleared within 3 weeks by a strong anti-viral CD8 T cells response that controls viral spread by both lytic and non-lytic mechanisms. Effector CD8 T cells can use these mechanisms to target resident CNS cells [9,54,55].…”

Myelin oligodendrocyte glycoprotein peptide-induced experimental allergic encephalomyelitis and T cell responses are unaffected by immunoproteasome deficiency

“…At first blush, neurons appear less likely targets for direct CD8 + T cell effects, because they express very low levels of MHC class I, and of other components of the class I antigen presentation pathway (Joly et al, 1991;Joly and Oldstone, 1992); however, MHC class I is up-regulated by neurons in response to injury or inflammation (Neumann et al, 1995;Neumann et al, 1997), potentially rendering them vulnerable to CD8 + T cell-mediated cytotoxicity. Indeed, blood-donor derived CD8 + cells can cause axon transection in cultured neurons (Medana et al, 2001). Thus, CD8 + lymphocytes also are implicated in the demyelination and pathogenesis of MS, but our understanding of the function of CD8 + T cells in the context of MS has been limited by the availability of appropriate animal models.…”