CD11c-Expressing Cells Affect Regulatory T Cell Behavior in the Meninges during Central Nervous System Infection

Abstract

Treg cells play an important role in the CNS during multiple infections as well as autoimmune inflammation, but the behavior of this cell type in the CNS has not been explored. In mice, infection with Toxoplasma gondii leads to a Th1-polarized parasite-specific effector T cell response in the brain. Similarly, the Treg cells in the CNS during T. gondii infection are Th1-polarized, exemplified by T-bet, CXCR3, and IFN-γ expression. Unlike effector CD4+ T cells, an MHC Class II tetramer reagent specific for T. gondii did not recognize Treg cells isolated from the CNS. Likewise, TCR sequencing revealed minimal overlap in TCR sequence between effector and regulatory T cells in the CNS. Whereas effector T cells are found in the brain parenchyma where parasites are present, Treg cells were restricted to the meninges and perivascular spaces. The use of intravital imaging revealed that activated CD4+ T cells within the meninges were highly migratory, while Treg cells moved more slowly and were found in close association with CD11c+ cells. To test whether the behavior of Tregs in the meninges is influenced by interactions with CD11c+ cells, mice were treated with anti-LFA-1 antibodies to reduce the number of CD11c+ cells in this space. The anti-LFA-1 treatment led to fewer contacts between Tregs and the remaining CD11c+ cells and increased the speed of Treg cell migration. These data suggest that Treg cells are anatomically restricted within the CNS and the interaction with CD11c+ populations regulates their local behavior during T. gondii infection.

Brains and Brawn: Toxoplasma Infections of the Central Nervous System and Skeletal Muscle

“…As with acute infections and most other type I responses, production of IFN-γ and other pro-inflammatory cytokines must be regulated by anti-inflammatory cytokines including IL-10 and IL-27, without which continued recruitment of highly activated immune cells into the brain leads to encephalitis independent of parasite burden [41–44]. The role of regulatory T cells has still to be fully assessed, however a recent study suggests that T regs inhabit a restricted niche in the meninges and perivascular space where they interact with CD11c expressing antigen-presenting cells [45]. Understanding the function and specificity of these interactions will be of future interest.…”

Astrocytes promote a protective immune response to brainToxoplasma gondiiinfection via IL-33-ST2 signaling

“…We detected ST2 on innate lymphoid cells (ILC2s) in the brain, as well as regulatory T cells (Tregs) (Figures S4A and S4B). But it is unclear if ILC2s would be relevant to monocyte recruitment during a Th1-dominated infection, and Tregs are spatially restricted from the parenchyma even after T. gondii infection 31 . ST2 mRNA has also been reported in microglia and astrocytes 49 .…”

“…Like IL-33 expression, IL-33 signaling during pathology in the brain likely differs from the periphery. ST2-expressing immune cells are physically separated from IL-33 expressing cells in the parenchyma by the BBB in a naïve state and would likely be unable to respond to initial insult 26,28-31 . Therefore, it is unknown if the generation of an immune response to brain pathology would necessitate IL-33 signaling on a brain-resident cell type.…”

IL-10 and ICOS differentially regulate T cell responses in the brain during chronicToxoplasma gondiiinfection

“…During chronic infection with T. gondii , both effector T cells and T regs recruited to the brain are capable of producing IL-10 [38]. Previously published results have shown a requirement for IL-10 signaling to limit fatal immunopathology in both the acute and chronic stages of infection [3, 21, 39, 40].…”