Neurons are MHC Class I-Dependent Targets for CD8 T Cells upon Neurotropic Viral Infection

Abstract

Following infection of the central nervous system (CNS), the immune system is faced with the challenge of eliminating the pathogen without causing significant damage to neurons, which have limited capacities of renewal. In particular, it was thought that neurons were protected from direct attack by cytotoxic T lymphocytes (CTL) because they do not express major histocompatibility class I (MHC I) molecules, at least at steady state. To date, most of our current knowledge on the specifics of neuron-CTL interaction is based on studies artificially inducing MHC I expression on neurons, loading them with exogenous peptide and applying CTL clones or lines often differentiated in culture. Thus, much remains to be uncovered regarding the modalities of the interaction between infected neurons and antiviral CD8 T cells in the course of a natural disease. Here, we used the model of neuroinflammation caused by neurotropic Borna disease virus (BDV), in which virus-specific CTL have been demonstrated as the main immune effectors triggering disease. We tested the pathogenic properties of brain-isolated CD8 T cells against pure neuronal cultures infected with BDV. We observed that BDV infection of cortical neurons triggered a significant up regulation of MHC I molecules, rendering them susceptible to recognition by antiviral CTL, freshly isolated from the brains of acutely infected rats. Using real-time imaging, we analyzed the spatio-temporal relationships between neurons and CTL. Brain-isolated CTL exhibited a reduced mobility and established stable contacts with BDV-infected neurons, in an antigen- and MHC-dependent manner. This interaction induced rapid morphological changes of the neurons, without immediate killing or impairment of electrical activity. Early signs of neuronal apoptosis were detected only hours after this initial contact. Thus, our results show that infected neurons can be recognized efficiently by brain-isolated antiviral CD8 T cells and uncover the unusual modalities of CTL-induced neuronal damage.

HLA Class I: An unexpected role in integrin β4 signaling in endothelial cells

“…This concept is consistent with recent data showing that engagement of MHC-I in neurons by the T cell receptors on CD8+ T cells alters the electrophysiological properties of neurons by increasing the frequency of grouped action potentials or bursts over the neuronal network [40]. This suggests that similar to crosslinking of HLA-I with antibodies, ligation of HLA-I with the T cell receptor elicits intracellular signals.…”

Borna Disease Virus Phosphoprotein Modulates Epigenetic Signaling in Neurons To Control Viral Replication

“…Primary neuronal cultures, virus infection, and plasmid transfection. Primary cortical neurons were prepared from Sprague-Dawley rat embryos at gestational day 17 by the papain dissociation method as described previously (18). At the end of the procedure, neurons were either directly plated on variable supports (glass coverslips or culture plates, depending on the experiments) or used for plasmid transfection before plating.…”

Migration et pathogénicité des lymphocytes T CD8 dans les maladies du système nerveux central

“…La plupart des cellules résidentes du système nerveux central comme les astrocytes, les neurones et les oligodendrocytes expriment, au moins dans un contexte inflammatoire, des molécules du complexe majeur d'histocompatibilité de classe I (CMH-I), et peuvent donc, théoriquement, être la cible des LT CD8 [11]. Contrastant avec la diversité du répertoire des LT CD4, plusieurs travaux concordants montrent le caractère oligoclonal des LT CD8 isolés du parenchyme cérébral [8].…”

“…D'autres modèles suggèrent ce rôle potentiellement délétère des LT CD8. Ainsi, des LT CD8 isolés de cerveaux de rats infectés par le Bornavirus 7 sont capables, in vitro, de reconnaître et de détruire spéci-fiquement les neurones infectés [11]. De même, dans le modèle d'infection par le virus de la chorioméningite 5 Le syndrome inflammatoire de reconstitution immunitaire (SIRI) est un é vé nement fré quent aprè s l'initiation d'un traitement antirétroviral chez des patients co-infecté s par le virus de l'immunodé ficience humaine (VIH).…”