Interferon y

Interferon y (IFNy) is another important molecule involved in the effector functions of cytotoxic T-cells. IFNy is a TH1 antiviral and immunomodulatory cytokine that is critically involved in host resistance to multiple pathogens. IFNy induces a wide range of effects on CNS cells, including macrophage activation, enhancement of leukocyte adhe sion, release of TNF-a and other cytokines, and upregula-tion of MHC expression on microglia and macrophages (Munoz-Fernandez and Fresno, 1998). We evaluated the role of IFNy in protecting neurons from virus-induced injury after infection with Theiler's virus. During viral infections, IFNy is produced by natural killer (NK) cells, CD4+, and CD8+ T-cells; however, the proportion of lymphocyte subsets responding to virus infection influences the contributions to IFNy-mediated protection. To determine the lymphocyte subsets that produce IFNy to maintain resistance, we used adoptive transfer strategies to generate mice with lymphocyte-specific deficiencies in IFNy production. We demonstrated that IFNy production by both CD4+ and CD8+ T-cell subsets is critical for resistance to Theiler's virus-induced demyelination and neurological disease, and that CD4+ T-cells make a greater contribution to IFNy-medi-ated protection. To determine the cellular targets of IFNy-mediated responses, we used adoptive transfer studies and bone marrow chimerism to generate mice in which either hematopoietic or somatic cells lacked the ability to express IFNy receptor. We demonstrated that IFNy receptor must be present on CNS glia, but not bone marrow-derived lymphocytes, in order to maintain resistance to Theiler's virus-induced demyelination (Murray et al., 2002). In addition, we found that both IFNy-- and IFNy+7+ mice of resistant MHC H-2b haplotype cleared Theiler's virus infection from spinal motor neurons, but whereas IFNy+7+ H-2b mice eventually cleared virus from the spinal cord white matter, IFNy-7- H-2b mice developed viral persistence in glial cells of the white matter and consequent spinal cord demyelination. Moreover, infection of susceptible H-2q haplotype IFNy-7- mice resulted in frequent deaths and severe neurological deficits within 11 to 16 days of infection as compared to infected IFNy+/- H-2q littermate controls and parental IFNy+7+ H-2q B10.Q controls (Fig. 16). Morphological analysis demonstrated severe injury to spinal cord neurons of IFNy-7- H-2q mice during early infection, with less than 20% of mice surviving 45 days after infection. More viral RNA was detected in the brain and spinal cord of IFNy-7- H-2q mice as compared to IFNy+/- H-2q or IFNy+7+ H-2q mice at 14 and 21 days after TMEV infection, and virus antigen was localized predominantly to spinal motor neurons in infected IFNy-7- H-2q mice. Virus antigen persisted in neurons in these mice for as long as 45 days after infection. IFNy deletion did not affect the humoral response directed against the virus; however, there was less expression of CD4, CD8, MHC class I, and MHC class II in the CNS of IFNy-7- H-2q mice as compared to IFNy+7+ H-2q mice. Finally, in vitro analysis of virus-induced death of NSC-34 spinal motor neurons and primary spinal motor neurons showed that IFNy exerted a neuropro-tective effect in the absence of other aspects of the immune response (Rodriguez et al., 2003) (Fig. 16). These findings suggest that IFNy plays a critical role in protecting spinal cord neurons from persistent infection and death, and that

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Figure 16 Interferon-y and IL-6 function as neuroprotective factors during Theiler's virus infection.

(A) Susceptible IFNy-- mice on an H-2q background exhibit dramatically reduced survival and significant neurological impairment after infection with Theiler's virus as compared to IFNy+fr H-2q mice and H-2b mice. (B) Spinal motor neurons infected in vitro with Theiler's virus exhibit profound apoptotic death. Treatment of these cells with IFNy or IL-6 rescued approximately half of the cells in culture without affecting the extent of infection. This suggests that IFNy and IL-6 directly stimulated the survival of spinal motor neurons. (C) After Theiler's virus infection astrocytes dramatically upregulate expression of IL-6, suggesting that they may be the local source of this factor necessary for protection of neurons. (D) IL-6, leukemia inhibitory factor (LIF), onco-statin M (OSM), and ciliary neurotrophic factor (CNTF) all share the gp130 receptor subunit, suggesting that the neuroprotective signaling effects of all of these molecules may be mediated in common by gp130.

the cells responsible for production of this protective IFNy appear to be cytotoxic T-cells. Thus, a model in which CD8+ T-cells attack and kill axons and neurons via perforin must also include CD8+ and CD4+ T-cells that release potentially neuroprotective cytokines that accelerate viral clearance while sparing irreplacable neurons.

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