The Function of Brain Th1-like regulatory T cells in Suppressing Lethal Immune Pathology and Neurological Deterioration during Cryptococcus neoformans Meningoencephalitis

Abstract

Abstract Infection-induced inflammation in the brain frequently drives severe immunopathology, resulting in lasting neurological sequelae or high mortality. Cryptococcus neoformans meningoencephalitis (CM) is one of the leading causes of neurological death worldwide. The pathology of CM is increasingly recognized to be driven by brain inflammation, especially in immunocompetent or immune reconstituted patients. The function of FOXP3+ regulatory T (Treg) cells in maintaining immune balance under these conditions is still controversial. Using a murine CM model, we found that Tregs massively accumulate in the mouse brain, suppressing lethal immune pathology and neurological deterioration during CM. Brain-infiltrating Tregs showed a CD44highCD62Llow activated status similar to effector T cells. Intriguingly, brain Tregs acquire a Th1-like phenotype, expressing transcription factor T-bet, IFN-γ, and chemokine receptor CXCR3. This Th1-like phenotype is critical for Treg accumulation in the brain during CM. Treg depletion using an anti-CD25 antibody intensifies CNS inflammation and results in deteriorated neurological symptoms and increased mortality. Mechanistically, we showed that CNS Tregs regulate activation of recruited monocyte-derived cells as well as cytokine production of T effector cells, both of which promote brain immunopathology during CM. Interestingly, Treg depletion only showed a minor effect on glia activation. Therapeutically, we showed that selectively enhancing Treg frequency through low-dose IL-2 treatment improves mice survival and neurological functions during CM. Our findings suggest that Tregs and their products may provide therapeutic opportunities for neuronal protection during CM.