Beneficial and Detrimental Effects of Regulatory T Cells in Neurotropic Virus Infections

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.

Keywords: Foxp3; animal models; central nervous system; demyelination; neuroinflammation; neurotropic viruses; regulatory T cells.

Figure 1

Types and functions of regulatory T cells (Treg). (a) There are two main types of Treg in humans and mice. Natural Treg (nTreg) are generated in the thymus from precursor T cells recognizing self-antigens presented by thymic antigen presenting cells (APC) via major histocompatibility complex (MHC) II molecules. The differentiation to the Treg phenotype is further influenced by local cytokines. nTreg express high levels of Helios and neuropilin-1 (Nrp1). Treg can also be generated de novo from naïve conventional cluster of differentiation (CD)4⁺ T cells in extrathymic tissues in the presence of interleukin (IL)-2, transforming growth factor (TGF)-β, and retinoic acid following T cell receptor (TCR) engagement. These induced Treg (iTreg) express low levels of Helios and Nrp1. Both Treg types are characterized by the expression of the transcription factor forkhead box protein P3 (Foxp3) and CD25. (b) Treg exert their suppressive function by various cell contact-dependent and -independent mechanisms. These include cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)-dependant suppression of B7-mediated co-stimulation of conventional T cells (Tconv), Lymphocyte activation gene 3 (LAG-3)-mediated suppression of dendritic cell (DC) maturation, IL-2 deprivation of other T cells through expression of high-affinity IL-2 receptors (IL2R), and generation of the immunosuppressive nucleotide adenosine by the ectoenzymes CD39 and CD73. Moreover, Treg secrete the anti-inflammatory cytokines IL-10, TGF-β, and IL-35, and induce apoptosis of inflammatory cells through granzyme/perforin secretion. Treg also shift macrophage polarization from M1 to the M2 type and induce the activity of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) in DCs.

Figure 2

Examples of interactions between regulatory T cells (Treg) and cells of the central nervous system (CNS). Treg influence the function and phenotype of resident CNS cells (black arrows, boxes). For instance, Treg alter microglial responses and suppress astrogliosis via secretion of amphiregulin (AREG) and cytokines, as well as through cell contact-dependent mechanisms. Moreover, Treg are involved in CNS regeneration: Treg-derived cellular network communication factor 3 (CCN3) promotes (re)myelination and differentiation of mature oligodendrocytes in vitro, and IL-10 induces proliferation and differentiation of neuronal stem cells in vivo. Neurons and microglia can induce Foxp3-expression and a regulatory phenotype in CD4⁺ T cells (green arrows) through secretion of TGF-β and B7/CD28 interaction or secretion of IL-10 in combination with low expression of co-stimulatory molecules, respectively. In addition, several factors secreted by glial and neuronal cells promote CNS infiltration of peripheral Treg (not depicted, for details see main text).