Treg Cells Modulate Neuroinflammation and Behavioral Deficits in Autism: Evidence from MR-based Genetic Analyses and Experimental Models

Background Autism spectrum disorder (ASD) is a neurodevelopmental condition increasingly linked to immune dysfunction and neuroinflammation. Regulatory T cells (Tregs), crucial in maintaining immune homeostasis, have been implicated in ASD pathogenesis, but their role in neuroimmune interactions and behavioral outcomes remains poorly understood.Methods We employed Mendelian Randomization (MR) to assess the causal relationship between Treg cells and ASD risk, using genetic data to infer causality. Additionally, we validated our findings in an ASD-like mouse model (BTBR mice) treated with an IL-2/JES6.1 complex to enhance Treg function. Neuroinflammation and behavioral outcomes were assessed in treated and control mice.Results MR analysis across two datasets identified inverse associations between certain Treg subsets, such as Resting CD4+ Tregs, with ASD risk, suggesting a protective role. Conversely, elevated levels of other Treg subsets were linked to increased ASD risk. Experimental treatment with IL-2/JES6.1 in BTBR mice significantly increased Treg populations, enhanced Treg activation, and improved social behaviors and repetitive behaviors. Furthermore, IL-2/JES6.1 treatment reduced neuroinflammatory markers, including microglial activation, indicating that Treg modulation impacts both immune responses and behavioral deficits in ASD.Conclusions This study demonstrates that Treg modulation can influence ASD pathogenesis through immune regulation and behavioral improvement. Our findings highlight the potential of Treg-targeted therapies for ASD treatment. Future studies should focus on the mechanistic pathways involved and explore the clinical applicability of these therapies.