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

Abstract

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.

T Cells Facilitate Recovery from Venezuelan Equine Encephalitis Virus-Induced Encephalomyelitis in the Absence of Antibody

“…This effect is most likely mediated primarily by IFN-␥ signaling within infected neurons, in similarity to what has been described in Sindbis virus, Borna virus, TMEV, and measles virus studies (7,23,38,42). However, we cannot rule out additional mechanisms.…”

Antiviral CD8 T Cells Recognize Borna Disease Virus Antigen Transgenically Expressed in either Neurons or Astrocytes

“…To address this question, we took advantage of the BDV mouse model system for the following main reasons: (i) the infection of mice with BDV is limited to the central and peripheral nervous systems (12; also our unpublished results); (ii) BDV infections are noncytolytic, and the virus is spread mostly if not exclusively by cell-to-cell contacts (29); (iii) CD8 T cells mediate immunity to BDV (14,16) 6 N-specific CD8 T cells each by the intracerebral (CD8 i.c. ; A and B) or the intravenous (CD8 i.v.…”

“…Indirect evidence suggesting that MHC-I expression occurs on neurons includes studies in knockout mice which revealed a role of MHC-I in the activity-dependent remodeling and plasticity of neuronal connections in the central nervous system (CNS) (24). The fact that certain viral CNS infections can be controlled by CD8 T cells is further indirect evidence for MHC-I expression on neurons (16,26,31,36,47). However, in most cases the specificity of the CD8 T cells responsible for virus clearance was ill defined, and the contributions of antigen presentation by other cell types remained unclear.…”

“…The majority of CD8 T cells in the CNS of diseased mice recognize a single H-2 k -restricted epitope (amino acid sequence 129 TELEISSI 136 ) of the BDV nucleoprotein (N) (44). TELEISSI-specific CD8 T cells use gamma interferon (IFN-␥) but not perforin to control the infection and to eliminate BDV from neurons (14,16).…”

Probiotics Applications in Autoimmune Diseases

“…This results in preventing the initiation of inflammation and progression of the autoimmune symptoms. Secondly, when dysfunctional lymphocytes are released into the mainstream, the immune system minimizes their ability to interact with triggers (antigens) through direct and indirect effects [6][7][8]. This results in a significant reduction in the severity of potential inflammatory response.…”