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

Gloria B Choi; Yeong S Yim; Helen Wong; Sangdoo Kim; Hyunju Kim; Sangwon V Kim; Charles A Hoeffer; Dan R Littman; Jun R Huh

doi:10.1126/science.aad0314

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

Science. 2016 Feb 26;351(6276):933-9. doi: 10.1126/science.aad0314. Epub 2016 Jan 28.

Authors

Gloria B Choi¹, Yeong S Yim¹, Helen Wong², Sangdoo Kim³, Hyunju Kim³, Sangwon V Kim⁴, Charles A Hoeffer⁵, Dan R Littman⁶, Jun R Huh⁷

Affiliations

¹ The McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
² Center for Neural Science, New York University, New York, NY 10003, USA. Institute for Behavioral Genetics, Department of Integrated Physiology, University of Colorado, Boulder, CO 80303, USA.
³ Division of Infectious Diseases and Immunology and Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
⁴ The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.
⁵ Center for Neural Science, New York University, New York, NY 10003, USA. Institute for Behavioral Genetics, Department of Integrated Physiology, University of Colorado, Boulder, CO 80303, USA. charles.hoeffer@colorado.edu dan.littman@med.nyu.edu jun.huh@umassmed.edu.
⁶ The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA. Howard Hughes Medical Institute, New York, NY 10016, USA. charles.hoeffer@colorado.edu dan.littman@med.nyu.edu jun.huh@umassmed.edu.
⁷ Division of Infectious Diseases and Immunology and Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA. charles.hoeffer@colorado.edu dan.littman@med.nyu.edu jun.huh@umassmed.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Blocking / immunology
Antibodies, Blocking / therapeutic use
Autism Spectrum Disorder / genetics
Autism Spectrum Disorder / immunology*
Autism Spectrum Disorder / prevention & control
Behavior, Animal
Behavioral Symptoms / immunology
Cerebral Cortex / abnormalities*
Cerebral Cortex / drug effects
Cerebral Cortex / immunology*
Female
Interleukin-17 / biosynthesis
Interleukin-17 / immunology*
Interleukin-17 / pharmacology
Male
Maternal-Fetal Exchange / immunology*
Mice
Mutation
Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology
Phenotype
Pregnancy
Prenatal Exposure Delayed Effects / immunology*
RNA, Messenger / biosynthesis
RNA, Messenger / genetics
Receptors, Retinoic Acid / genetics
Receptors, Retinoic Acid / immunology
Retinoic Acid Receptor gamma
Signal Transduction
Th17 Cells / drug effects
Th17 Cells / immunology*

Substances

Antibodies, Blocking
Il17a protein, mouse
Interleukin-17
Nuclear Receptor Subfamily 1, Group F, Member 3
RNA, Messenger
Receptors, Retinoic Acid

Abstract

Publication types

MeSH terms

Substances

Grants and funding