Harnessing Regulatory T cells to Suppress Pathological Immune Response during Cryptococcus neoformans Meningoencephalitis

Abstract

Abstract Central nervous systems (CNS) infections are marked by high mortality or frequently lasting neurologic disorders in the survivors. Cryptococcus neoformans meningoencephalitis (CM) is one of the leading causes of infectious neurological death. Many CM patients develop severe neurological symptoms despite evidence of ongoing immune response and fungal eradication, suggesting a dysregulated pathological host response. Our objective is to test whether and how regulatory T cells (Treg) maintain immune balance in CM and whether they could be used therapeutically to limit inflammatory CNS damage. Using a murine CM model, we found Foxp3+ Treg massively accumulate in the infected brain. They acquire a Th1-like phenotype, expressing transcription factor T-bet, IFN-γ, and chemokine receptor CXCR3. This phenotype is critical for Treg accumulation in the CM brain. Treg depletion using anti-CD25 antibody results in deteriorated neurological symptoms and increased mouse mortality. Mechanistically, we found that brain-infiltrating Treg express immune suppressive molecules, such as IL-10 and tissue repair molecules, such as Amphiregulin compared to effector T cells. Single-cell RNA seq analysis showed broad cross-talk between brain Tregs with infiltrating T cell, monocyte-derived cells, and brain resident glial cells. Treg depletion resulted in increased activation of pathological T cells and monocyte-derived cells, promoting brain immunopathology during CM. Selectively enhancing Treg through low-dose IL-2 treatment improves mice survival and neurological function readouts. Taken together, our findings suggest that Treg limit pathological CNS inflammation and may provide the therapeutic opportunity for CM patients.