| First Author | Stubblefield Park SR | Year | 2011 |
| Journal | J Virol | Volume | 85 |
| Issue | 7 | Pages | 3664-76 |
| PubMed ID | 21270150 | Mgi Jnum | J:343106 |
| Mgi Id | MGI:7562608 | Doi | 10.1128/JVI.01496-10 |
| Citation | Stubblefield Park SR, et al. (2011) T cell-, interleukin-12-, and gamma interferon-driven viral clearance in measles virus-infected brain tissue. J Virol 85(7):3664-76 |
| abstractText | Genetic studies with immunocompetent mice show the importance of both T cells and gamma interferon (IFN-gamma) for survival of a measles virus (MV) challenge; however, the direct role of T cells and IFN-gamma within the MV-infected brain has not been addressed. Organotypic brain explants represent a successful ex vivo system to define central nervous system (CNS)-specific mechanisms of leukocyte migration, activation, and MV clearance. Within the heterogeneous, brain-derived, primed leukocyte population which reduced MV RNA levels in brain explants by 60%, CD3 T cells are the active antiviral cells, as purified CD3-positive cells are highly antiviral and CD3-negative leukocytes are unable to reduce the viral load. Neutralization of CCL5 and CXCL10 decreases leukocyte migration to areas of infection by 70%. However, despite chemokines directing the migration of T cells to infected neurons, chemokine neutralization revealed that migration is not required for viral clearance, suggesting a cytokine-mediated antiviral mechanism. In accordance with our hypothesis, the ability of leukocytes to clear the virus is abrogated when explants are treated with anti-IFN-gamma neutralizing antibodies. IFN-gamma applied to infected slices in the absence of primed leukocytes reduces the viral load by more than 80%; therefore, in brain tissue, IFN-gamma is both necessary and sufficient to clear MV. Secretion of IFN-gamma is stimulated by interleukin-12 (IL-12) in the brain, as neutralization of IL-12 results in loss of antiviral activity and stimulation of leukocytes with IL-12/IL-18 enhances their immune effector function of viral clearance. MV-primed leukocytes can reduce both West Nile and mouse hepatitis viral RNAs, indicating that cytokine-mediated viral clearance occurs in an antigen-independent manner. The IFN-gamma signal is transduced within the brain explant by the Jak/STAT signaling pathway, as inhibition of Jak kinases results in a loss of antiviral activity driven by either brain-derived leukocytes or recombinant IFN-gamma. These results reveal that primed T cells directly act to clear MV infection of the brain by using a noncytolytic IL-12- and IFN-gamma-dependent mechanism in the CNS and that this mechanism relies upon Jak/STAT signaling. |
