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JC virus-specific cytotoxic T lymphocytes in individuals with progressive multifocal leukoencephalopathy
I J Koralnik1, R A Du Pasquier, N L Letvin
1Department of Neurology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. ikoralni@caregroup.harvard.edu
Insights
Cytotoxic T lymphocytes (CTL) targeting the JC virus (JCV) were found in survivors of progressive multifocal leukoencephalopathy (PML). The absence of these JCV-specific CTL correlated with fatal outcomes in PML patients.
Area of Science:
- Neuroimmunology
- Virology
- Immunology
Background:
- Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system.
- PML is caused by the reactivation of the JC virus (JCV) in immunosuppressed individuals.
- The specific immune mechanisms controlling JCV replication in PML are not fully understood.
Purpose of the Study:
- To investigate JCV-specific cellular immune responses in patients with PML.
- To determine the role of immune responses in the containment of JCV.
- To identify potential prognostic markers for PML clinical management.
Main Methods:
- Analysis of peripheral blood mononuclear cells (PBMC) from PML patients and controls.
- Stimulation of PBMC with JCV antigens.
- Assessment of cell-mediated cytotoxicity against JCV-expressing cells.
- Identification of mediating immune cells (CD8+ T lymphocytes) and their restriction (MHC class I).
Main Results:
- JCV-specific cytotoxic T lymphocytes (CTL) were detected in HIV-infected PML survivors and one HIV-uninfected PML patient.
- These CTL lysed autologous B-lymphoblastoid cell lines expressing JCV T regulatory protein or VP1.
- JCV-specific CTL were absent in HIV-infected PML patients with progressive neurological disease and fatal outcomes.
Conclusions:
- JCV-specific cellular immune responses, particularly CTL, appear crucial for containing PML.
- The presence of JCV-specific CTL may serve as a favorable prognostic marker in PML patients.
- Understanding these immune responses could inform future therapeutic strategies for PML.
Abstract:
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by a reactivation of the polyomavirus JC (JCV) within a setting of immunosuppression. The nature of the immune response that contains replication of this virus is unknown. We have explored JCV-specific cellular immune responses in patients with PML and control subjects. JCV antigen-stimulated peripheral blood mononuclear cells (PBMC) of four human immunodeficiency virus (HIV)-infected patients who were survivors of PML and one HIV-uninfected patient recently diagnosed with PML lysed autologous B-lymphoblastoid cell lines expressing either the JCV T regulatory protein or the VP1 major capsid protein. This lysis was mediated by CD8(+) T lymphocytes and was major histocompatibility complex class I restricted. These cells were therefore cytotoxic T lymphocytes (CTL). JCV-specific CTL could not be detected in PBMC of three HIV-infected PML patients who had progressive neurologic disease and an eventual fatal outcome. These data suggest that the JCV-specific cellular immune response may play a crucial role in the containment of PML. This finding may also prove useful as a favorable prognostic marker in the clinical management of these patients.