Foxp3+ regulatory T cells (Tregs) restrain inflammation and protect brain damage during cryptococcal meningoencephalitis 3339

Abstract Description Cryptococcus meningoencephalitis (CM) is a lethal fungal disease. Clinical observations and animal model studies document that unchecked inflammation in the brain contributes to the disease’s progression. Regulatory T cells (Tregs) are critical for maintaining immune balance, yet their precise role and mechanisms in preventing pathological neuroinflammation during CM, as well as their therapeutic potential, remain poorly understood. Our study reveals that Tregs are present in the CSF of CM patients and are accumulated in mouse brain over the course of disease progression; Treg depletion exacerbates Th1-driven brain inflammation, worsens neurological symptoms, and accelerates mortality, despite a reduction in fungal burden; Brain single-cell RNA-seq analysis shows high expression of CCR8 on Tregs and anti-CCR8 treatment significantly reduced Treg accumulation in the brain, revealing Treg recruitment in the brain depends on CCR8-CCL1 axis; Furthermore, brain-infiltrating Tregs suppress inflammation via the anti-inflammatory cytokine IL-10, while their production of Areg promotes IFN-γ production by Teffs, in part reducing Treg efficiency in suppressing CM inflammation. Finally, a promising Treg-enhancing immunotherapy using low-dose IL-2 treatment improves mice survival and neurological function significantly. Taken together, our results identify that CCR8-CCL1-recruited Tregs in the brain could serve as a potential therapeutic strategy to mitigate immunopathology during CM. Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)