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


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          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.

          Author Summary

          When a virus infects the brain, it is important to quickly block viral replication without causing excessive damage to neurons, which are not easily renewed. Cytotoxic T lymphocytes (CTL) are one of the main actors for virus elimination. However, the question of whether CTL are indeed capable of destroying infected neurons remains controversial. For this work, we analyzed the characteristics of interactions between infected neurons and CTL using neurotropic Borna disease virus (BDV). This virus infects neurons and triggers severe inflammation in the brain. We isolated CTL directly from the brains of rats infected with BDV and analyzed their interaction with primary cultures of neurons. Using live-cell fluorescence microscopy, we observed that CTL were arrested upon encounter with infected neurons and that they established stable contacts with them. Thereafter, infected neurons exhibited rapid changes in permeability but remained alive and electrically active for several hours, before ultimately being destroyed. Our study shows that neurons can indeed be recognized by CTL, an important observation for a better understanding of the physiopathology of virus-induced brain inflammation. In addition, it reveals that neurons are relatively resistant to CTL-induced killing, which may open a window of opportunity for new treatments.

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          Most cited references65

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                Author and article information

                Role: Editor
                PLoS Pathog
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                November 2011
                November 2011
                17 November 2011
                : 7
                : 11
                : e1002393
                [1 ]Inserm, U1043, Toulouse, France
                [2 ]CNRS, U5282, Toulouse, France
                [3 ]Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
                [4 ]INSERM, U862 and Université Bordeaux 2, Bordeaux, France
                The Fox Chase Cancer Center, United States of America
                Author notes

                ¤a: Current address: Gladstone Institute of Neurological Diseases, San Francisco, California, United States of America

                ¤b: Current address: Millegen SA, Toulouse, France

                Conceived and designed the experiments: DGD ES GC RL. Performed the experiments: GC ES CM VD FF GMB. Analyzed the data: GC ES CM DGD. Contributed reagents/materials/analysis tools: GLM. Wrote the paper: GC DGD.

                Chevalier et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                : 26 July 2011
                : 7 October 2011
                Page count
                Pages: 14
                Research Article
                Immune Cells
                T Cells
                Immunity to Infections
                Adaptive Immunity
                Immune Defense
                Immune Privilege
                Innate Immunity
                Viral Classification
                RNA viruses
                Viral Transmission and Infection
                Viral Clearance
                Animal Models of Infection
                Viral Persistence and Latency
                Host-Pathogen Interaction
                Model Organisms
                Animal Models
                Molecular Cell Biology
                Cellular Types
                Flow Cytometry
                Cell Death
                Cellular Stress Responses
                Neurobiology of Disease and Regeneration

                Infectious disease & Microbiology
                Infectious disease & Microbiology


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