Abstract
We earlier established a model of a persistent viral CNS infection using two week old immunologically normal (genetically unmodified) mice and recombinant measles virus (MV). Using this model infection we investigated the role of regulatory T cells (Tregs) as regulators of the immune response in the brain, and assessed whether the persistent CNS infection can be modulated by manipulation of Tregs in the periphery. CD4+ CD25+ Foxp3+ Tregs were expanded or depleted during the persistent phase of the CNS infection, and the consequences for the virus-specific immune response and the extent of persistent infection were analyzed. Virus-specific CD8+ T cells predominantly recognising the H-2Db-presented viral hemagglutinin epitope MV-H22–30 (RIVINREHL) were quantified in the brain by pentamer staining. Expansion of Tregs after intraperitoneal (i.p.) application of the superagonistic anti-CD28 antibody D665 inducing transient immunosuppression caused increased virus replication and spread in the CNS. In contrast, depletion of Tregs using diphtheria toxin (DT) in DEREG (depletion of regulatory T cells)-mice induced an increase of virus-specific CD8+ effector T cells in the brain and caused a reduction of the persistent infection. These data indicate that manipulation of Tregs in the periphery can be utilized to regulate virus persistence in the CNS.
Highlights
The role of CD4+ CD25+ regulatory T cells (Tregs) in autoimmune and pathogen-induced immune responses has been studied intensively during recent years
Lymphocytes were isolated from 6 draining cervical lymph nodes (LN), the spleen, and the brain of MVinfected and control (i.c. injected PBS) animals
Our results indicate that the immune system keeps the ‘‘hidden’’ persistent viral CNS infection under permanent control
Summary
The role of CD4+ CD25+ regulatory T cells (Tregs) in autoimmune and pathogen-induced immune responses has been studied intensively during recent years. During acute viral infections depletion of Tregs was found to prevent the development of exhausted T cells and to improve the immune response. The important protective role of Tregs against an overshooting immune response in the CNS became obvious in animal models of stroke and experimental autoimmune encephalitis [10,11], and human immunodeficiency virus-1 (HIV-1)-associated neuro-degeneration, where they reduce astrogliosis and microglia-mediated inflammation [12]. Some viruses even developed the strategy to support the expansion of Tregs in order to suppress anti-viral cytotoxic T cell (CTL) responses and to limit viral immunopathogenesis [13,14,15,16,17,18]. Defects in regulation of numbers or the activity of Tregs are involved in a number of human autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, and multiple sclerosis [19]
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