Maternal immune activation imprints a regulatory T cell deficiency in offspring that drives an autism-like phenotype

Ellul, P.; Fourcade, g.; Mhanna, V.; Coatnoan, N.; Bodula, S.; Seilhean, D.; Mouton, L.; Marguerit, G.; Delorme, R.; Mi, T.; Youngblood, B.; Rosenzwajg, M.; Tchitcheck, N.; Klatzmann, D.

doi:10.1101/2025.01.06.631430

bioRxiv · 10.1101/2025.01.06.631430

Maternal immune activation imprints a regulatory T cell deficiency in offspring that drives an autism-like phenotype

Ellul, P.·Fourcade, g.·Mhanna, V.·Coatnoan, N.·Bodula, S.·Seilhean, D.·Mouton, L.·Marguerit, G.·Delorme, R.·Mi, T.·Youngblood, B.·Rosenzwajg, M.·Tchitcheck, N.·Klatzmann, D.

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Abstract

Maternal immune activation (MIA) triggers an IL-17-driven autism spectrum disorder (ASD) in mouse and human offspring. While regulatory T cells (Tregs) regulate Th17 cells, their involvement in MIA and ASD pathogenesis is unknown. At the maternal level, we show that Treg stimulation suppresses interleukin-17 (IL-17) production and prevents ASD-like behaviors in offspring. At the offspring level, we show that MIA imprints a systemic and brain Treg deficiency, as evidenced by alterations in the methylome, transcriptome, and functional assays. This deficiency promotes brain inflammation, characterized by infiltration of IL-17-producing cells and neutrophils into the meninges and alterations in cortical brain structure. Stimulation of offspring Tregs with interleukin-2 reversed brain inflammation and cured established ASD-like behaviors. Thus, MIA-induced ASD is a neuroimmune disorder that can be reversed by immunomodulation. One sentence abstractMaternal immune activation during pregnancy imprints a Treg deficiency in offspring that perpetuates brain inflammation and an autism-like phenotype, which can be reversed by Treg stimulation.

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Ellul, P., Fourcade, g., Mhanna, V., Coatnoan, N., Bodula, S., Seilhean, D., Mouton, L., Marguerit, G., Delorme, R., Mi, T., Youngblood, B., Rosenzwajg, M., Tchitcheck, N., Klatzmann, D.. 2025-01-08. Maternal immune activation imprints a regulatory T cell deficiency in offspring that drives an autism-like phenotype. https://doi.org/10.1101/2025.01.06.631430

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