The functional avidity of virus‐specific CD8<sup>+</sup> T cells is down‐modulated in Borna disease virus‐induced immunopathology of the central nervous system

Engelhardt, Karin R.; Richter, Kirsten; Baur, Karen; Staeheli, Peter; Hausmann, Jürgen

doi:10.1002/eji.200425232

Cited by 13 publications

(9 citation statements)

References 40 publications

(39 reference statements)

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“…We previously showed that brain-derived mononuclear cell preparations isolated from wild-type MRL mice infected as newborns contain around 30% CD8 T cells and around 10 to 15% CD4 T cells at the peak of neurological disease (27). We also showed previously that around 30% of the CD8 T cells were TELEISSI specific when labeled with a TELEISSI-H-2K k tetramer directly after isolation (14). In brain mononuclear cell preparations of MRL-GKO mice (n ϭ 19) infected at day 77, we found 38% CD8 T cells, of which 25% were TELEISSI specific, as judged by ex vivo tetramer staining (data not shown).…”

Section: Resultsmentioning

confidence: 83%

CD8 T Cells Require Gamma Interferon To Clear Borna Disease Virus from the Brain and Prevent Immune System-Mediated Neuronal Damage

Hausmann¹,

Pagenstecher

Baur³

et al. 2005

J Virol

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Borna disease virus (BDV) frequently causes meningoencephalitis and fatal neurological disease in young but not old mice of strain MRL. Disease does not result from the virus-induced destruction of infected neurons. Rather, it is mediated by H-2 k -restricted antiviral CD8 T cells that recognize a peptide derived from the BDV nucleoprotein N. Persistent BDV infection in mice is not spontaneously cleared. We report here that N-specific vaccination can protect wild-type MRL mice but not mutant MRL mice lacking gamma interferon (IFN-␥) from persistent infection with BDV. Furthermore, we observed a significant degree of resistance of old MRL mice to persistent BDV infection that depended on the presence of CD8 T cells. We found that virus initially infected hippocampal neurons around 2 weeks after intracerebral infection but was eventually cleared in most wild-type MRL mice. Unexpectedly, young as well as old IFN-␥-deficient MRL mice were completely susceptible to infection with BDV. Moreover, neurons in the CA1 region of the hippocampus were severely damaged in most diseased IFN-␥-deficient mice but not in wild-type mice. Furthermore, large numbers of eosinophils were present in the inflamed brains of IFN-␥-deficient mice but not in those of wild-type mice, presumably because of increased intracerebral synthesis of interleukin-13 and the chemokines CCL1 and CCL11, which can attract eosinophils. These results demonstrate that IFN-␥ plays a central role in host resistance against infection of the central nervous system with BDV and in clearance of BDV from neurons. They further indicate that IFN-␥ may function as a neuroprotective factor that can limit the loss of neurons in the course of antiviral immune responses in the brain.

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Section: Resultsmentioning

confidence: 83%

CD8 T Cells Require Gamma Interferon To Clear Borna Disease Virus from the Brain and Prevent Immune System-Mediated Neuronal Damage

Hausmann¹,

Pagenstecher

Baur³

et al. 2005

J Virol

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“…The transient loss of tetramer staining has been described in murine systems and was attributed to T cell receptor (TCR) down-regulation or decreased binding affinity (Engelhardt et al, 2005;Kambayashi et al, 2001). A recent study examining tetramer expression in humans infected with hepatitis B also reported tetramer negative cells that responded to viral peptide as measured by production of intracellular IFN-γ (Reignat et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Memory lineage relationships in HTLV-1-specific CD8+ cytotoxic T cells

Johnson-Nauroth¹,

Graber²,

Yao³

et al. 2006

Journal of Neuroimmunology

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Cytotoxic memory T cells play a critical role in combating viral infections; however, in some diseases they may contribute to tissue damage. In HAM/TSP, HTLV-1 Tax 11-19+ cells proliferate spontaneously in vitro and can be tracked using the Tax 11-19 MHC Class I tetramer. Immediately ex vivo, these cells were a mix of CD45RA − /CCR7 − T EM and CD45RA + /CCR7 − T Diff memory CTL. The subsequent proliferating Tax 11-19 tetramer+ population expressed low levels of IL-7Rα, failed to respond to IL-7 and IL-15, and did not develop a T CM phenotype. Thus, chronic exposure to viral antigen may result in a sustained pool of T EM cells that home to the CNS and mediate the spinal cord pathology seen in this disease.

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“…The CD8 ϩ T-cell responses induced after viral infection have previously been investigated with other animal viruses, including influenza virus, lymphocytic choriomeningitis virus (LCMV), mouse hepatitis virus (MHV), and Borna disease virus (11,14,35,47,58). Among these models, the detailed T-cell V␤ repertoire in the CNS was described only in the MHV model (46).…”

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confidence: 99%

Predominant Clonal Accumulation of CD8⁺T Cells with Moderate Avidity in the Central Nervous Systems of Theiler's Virus-Infected C57BL/6 Mice

Kang

Kim

2010

J Virol

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Induction of antigen-specific CD8؉ T cells bearing a high-avidity T-cell receptor (TCR) is thought to be an important factor in antiviral and antitumor immune responses. However, the relationship between TCR diversity and functional avidity of epitope-specific CD8 ؉ T cells accumulating in the central nervous system (CNS) during viral infection is unknown. Hence, analysis of T-cell diversity at the clonal level is important to understand the fate and function of virus-specific CD8 ؉ T cells. In this study, we examined the V␤ diversity and avidity of CD8 ؉ T cells specific to the predominant epitope (VP2 121-130 ) of Theiler's murine encephalomyelitis virus. We found that V␤6 ؉ CD8 ؉ T cells, associated with epitope specificity, predominantly expanded in the CNS during viral infection. Further investigations of antigen-specific V␤6 ؉ CD8 ؉ T cells by CDR3 spectratyping and sequencing indicated that distinct T-cell clonotypes are preferentially increased in the CNS compared to the periphery. Among the epitope-specific V␤6 ؉ CD8 ؉ T cells, MGX-J␤1.1 motif-bearing cells, which could be found at a high precursor frequency in naïve mice, were expanded in the CNS and tightly associated with gamma interferon production. These T cells displayed moderate avidity for the cognate epitope rather than the high avidity normally observed in memory/effector T cells. Therefore, our findings provide new insights into the CD8 ؉ T-cell repertoire during immune responses to viral infection in the CNS.

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The functional avidity of virus‐specific CD8⁺ T cells is down‐modulated in Borna disease virus‐induced immunopathology of the central nervous system

Cited by 13 publications

References 40 publications

CD8 T Cells Require Gamma Interferon To Clear Borna Disease Virus from the Brain and Prevent Immune System-Mediated Neuronal Damage

CD8 T Cells Require Gamma Interferon To Clear Borna Disease Virus from the Brain and Prevent Immune System-Mediated Neuronal Damage

Memory lineage relationships in HTLV-1-specific CD8+ cytotoxic T cells

Predominant Clonal Accumulation of CD8⁺T Cells with Moderate Avidity in the Central Nervous Systems of Theiler's Virus-Infected C57BL/6 Mice

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The functional avidity of virus‐specific CD8+ T cells is down‐modulated in Borna disease virus‐induced immunopathology of the central nervous system

Cited by 13 publications

References 40 publications

CD8 T Cells Require Gamma Interferon To Clear Borna Disease Virus from the Brain and Prevent Immune System-Mediated Neuronal Damage

CD8 T Cells Require Gamma Interferon To Clear Borna Disease Virus from the Brain and Prevent Immune System-Mediated Neuronal Damage

Memory lineage relationships in HTLV-1-specific CD8+ cytotoxic T cells

Predominant Clonal Accumulation of CD8+T Cells with Moderate Avidity in the Central Nervous Systems of Theiler's Virus-Infected C57BL/6 Mice

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The functional avidity of virus‐specific CD8⁺ T cells is down‐modulated in Borna disease virus‐induced immunopathology of the central nervous system

Predominant Clonal Accumulation of CD8⁺T Cells with Moderate Avidity in the Central Nervous Systems of Theiler's Virus-Infected C57BL/6 Mice