The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring

TLDR

Viral infection during pregnancy is linked to higher autism risk in offspring, a finding modeled in rodents via maternal immune activation, yet the key immune cells involved remain unidentified. The study uses genetic mutants and blocking antibodies to demonstrate that maternal RORγt‑dependent TH17 cells and IL‑17a are necessary for MIA‑induced behavioral abnormalities in offspring. MIA causes an IL‑17a‑dependent abnormal cortical phenotype in the fetal brain, and targeting maternal TH17 cells could reduce the risk of inflammation‑induced ASD‑like outcomes in offspring.

Abstract

Viral infection during pregnancy has been correlated with increased frequency of autism spectrum disorder (ASD) in offspring. This observation has been modeled in rodents subjected to maternal immune activation (MIA). The immune cell populations critical in the MIA model have not been identified. Using both genetic mutants and blocking antibodies in mice, we show that retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt)-dependent effector T lymphocytes [for example, T helper 17 (TH17) cells] and the effector cytokine interleukin-17a (IL-17a) are required in mothers for MIA-induced behavioral abnormalities in offspring. We find that MIA induces an abnormal cortical phenotype, which is also dependent on maternal IL-17a, in the fetal brain. Our data suggest that therapeutic targeting of TH17 cells in susceptible pregnant mothers may reduce the likelihood of bearing children with inflammation-induced ASD-like phenotypes.