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Perforin-mediated effector function within the central nervous system requires IFN-gamma-mediated MHC up-regulation
Cornelia C Bergmann1, Beatriz Parra, David R Hinton
1Department of Neurology, Keck School of Medicine, University of California, Los Angeles, CA 90033, USA.
Journal of Immunology (Baltimore, Md. : 1950)
|March 11, 2003
Summary
Interferon-gamma (IFN-γ) is crucial for CD8(+) T cells to control mouse hepatitis virus in the central nervous system (CNS). IFN-γ also enhances MHC expression, supporting T cell function and regulating demyelination.
Area of Science:
- Immunology
- Neurovirology
- Cellular Biology
Background:
- CD8(+) T cells are vital for controlling neurotropic JHMV infections in the CNS.
- Perforin and IFN-γ are key antiviral mechanisms with distinct roles in clearing infected cells.
- Evaluating effector functions of CD8(+) T cells requires specific models to understand their roles in pathogenesis.
Purpose of the Study:
- To investigate the specific roles of perforin and IFN-γ in CD8(+) T cell-mediated control of JHMV infection in the CNS.
- To analyze the impact of these effector functions on viral pathogenesis and demyelination.
- To understand the interplay between IFN-γ, MHC expression, and T cell function in the CNS.
Main Methods:
- Utilized perforin- and IFN-γ-deficient mice (PKO/GKO) to model JHMV infection.
- Adoptive transfer of CD8(+) T cells from wild-type, perforin-deficient, or IFN-γ-deficient donors into PKO/GKO recipients.
- Assessed viral load, immune cell infiltration (CD8(+) and CD4(+) T cells), MHC class I and II expression on microglia, and demyelination.
Main Results:
- PKO/GKO mice without functional perforin or IFN-γ succumbed to lethal encephalomyelitis, despite increased CD8(+) T cell infiltration.
- CD8(+) T cells from perforin-deficient and wild-type donors reduced viral replication in PKO/GKO recipients.
- IFN-γ-deficient CD8(+) T cells failed to control viral replication, highlighting IFN-γ's direct antiviral role and its necessity for MHC expression, which is critical for T cell function in the CNS.
Conclusions:
- IFN-γ exhibits direct antiviral activity against JHMV in the CNS.
- IFN-γ is essential for up-regulating MHC surface expression, thereby enabling local CD8(+) T cell effector functions in the CNS.
- IFN-γ plays a critical role in regulating the balance between viral replication, CD8(+) T cell responses, and demyelination during JHMV-induced encephalomyelitis.