Abstract
Neurotropic viruses infect the central nervous system (CNS) and cause acute or chronic neurologic disabilities. Regulatory T cells (Treg) play a critical role for immune homeostasis, but may inhibit pathogen-specific immunity in infectious disorders. The present review summarizes the current knowledge about Treg in human CNS infections and their animal models. Besides dampening pathogen-induced immunopathology, Treg have the ability to facilitate protective responses by supporting effector T cell trafficking to the infection site and the development of resident memory T cells. Moreover, Treg can reduce virus replication by inducing apoptosis of infected macrophages and attenuate neurotoxic astrogliosis and pro-inflammatory microglial responses. By contrast, detrimental effects of Treg are caused by suppression of antiviral immunity, allowing for virus persistence and latency. Opposing disease outcomes following Treg manipulation in different models might be attributed to differences in technique and timing of intervention, infection route, genetic background, and the host’s age. In addition, mouse models of virus-induced demyelination revealed that Treg are able to reduce autoimmunity and immune-mediated CNS damage in a disease phase-dependent manner. Understanding the unique properties of Treg and their complex interplay with effector cells represents a prerequisite for the development of new therapeutic approaches in neurotropic virus infections.
Highlights
A variety of viruses are able to infect the central nervous system (CNS) and contribute to neurologic diseases in humans and animals worldwide
Defects in the gene coding for the regulatory T cell (Treg)-specific transcription factor forkhead box protein P3 (Foxp3) lead to an aggressive and fatal autoimmune disorder known as immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) in humans and a comparable systemic lymphoproliferative disease in scurfy mutant mice [42,43]
Due to several limitations of studies in human subjects, animal models of viral CNS diseases have been employed to elucidate the relevance of certain immunophenotypes and their involvement in the pathogensis of infectious diseases
Summary
A variety of viruses are able to infect the central nervous system (CNS) and contribute to neurologic diseases in humans and animals worldwide. Virus infection of the CNS typically leads to lymphocytic inflammation, glial activation, and tissue damage, including necrosis and demyelination (Table 1). Mononuclear infiltrates, hemorrhages, necrosis, intranuclear inclusion bodies (Cowdry type A) in neurons and glial cells. Vasculopathy, vascular fibrinoid necrosis and thrombosis, necrosis, hemorrhagic infarcts, demyelination, intranuclear inclusion bodies (Cowdry type A) in glial and ependymal cells [12,13,14] [15,16,17]. Regulatory T cells (Treg), a cluster of differentiation (CD)4+ T cell subset with immunosuppressive and immunomodulatory functions, are principle regulators of immune reactions and mediators of peripheral tolerance They contribute to tissue homeostasis under steady state conditions and regulate immune responses in inflammatory diseases [33,34]. The present review summarizes the current knowledge on Treg involvement in human CNS infections and the effects of Treg manipulation in experimental models of human neutrotropic virus infection and virus-induced demyelination
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