Discovery of Brain-Resident Immune Cells Linked to Autism Spectrum Disorder: γδT Cells Accumulate in ASD Model Mice and Contribute to Abnormal Social Behavior

〇 Autism spectrum disorder (ASD) is a neurodevelopmental condition with many aspects of its pathogenesis still unclear. Recently, interactions between the brain and immune cells have attracted increasing attention.

〇 Using a mouse model of ASD, researchers discovered that γδT cells producing IL-17A accumulate in the developing brain via CXCL16 signaling, promoting ASD-like social behavioral abnormalities.

〇 This finding provides a novel perspective on understanding ASD not only from a neurological standpoint but also through interactions between the nervous and immune systems, offering potential for developing new diagnostic and therapeutic approaches targeting immune cells.

(Overview)

Traditionally, autism spectrum disorder (ASD) has been considered primarily a neurodevelopmental disorder caused by abnormalities in neurons and neural circuits. In recent years, however, changes in the immune system—such as maternal infection or inflammation during pregnancy—have been recognized as potentially affecting brain development and behavior. Nevertheless, how immune cells influence brain function and contribute to social behavioral abnormalities in genetically based ASD has remained poorly understood.

In this study, a research group revealed a novel mechanism in a mouse model of ASD that recapitulates chromosomal abnormalities associated with human ASD: specific immune cells accumulate in the brain during development and promote abnormal social behaviors.

The research team, led by Associate Professor Minako Ito of the Research Institute for Microbial Diseases at Osaka University, graduate student Natsumi Takayama (at the time), Professor Toru Takumi of Kobe University, Professor Manabu Makinodan of Kumamoto University, Professor Kazuhiko Yamamuro of Nara Medical University, and Professor Akira Makino of Hamamatsu University School of Medicine, analyzed the brains of ASD model mice during development and discovered an increased presence of γδT cells compared to normal mice. Furthermore, they found that microglia (※4), immune cells in the brain, produce CXCL16, which recruits γδT cells into the brain. These accumulated γδT cells were found to produce IL-17A, a molecule involved in inflammation. Notably, when the activity of γδT cells or IL-17A was blocked using antibodies, the social behavioral abnormalities observed in ASD model mice improved.

This discovery shifts the understanding of ASD from being solely a neuronal abnormality to one involving interactions between the brain and immune cells. It is expected to contribute to the future development of novel diagnostic and therapeutic strategies for ASD targeting brain-resident immune cells or the IL-17A signaling pathway.

This research was published in the U.S. scientific journal "Science Immunology" on June 19, 2026 (U.S. Eastern Time).

[Background and Context]

Autism spectrum disorder (ASD) is a developmental disorder characterized by difficulties in social interaction and communication, as well as strong interests and repetitive behaviors. The number of individuals diagnosed with ASD has been increasing in recent years, yet the underlying causes remain largely unknown, and no fundamental treatments have been established.

ASD has traditionally been thought to arise mainly from abnormalities in brain neurons and neural circuits. However, recent studies suggest that immune cells, which play a role in protecting the body, may also influence brain development and behavior. In particular, changes in immune status due to maternal infection or inflammation during pregnancy have been reported to affect fetal and childhood brain development. Most previous studies, however, have focused on environmental factors such as infection or inflammation. While genetic factors are known to contribute to ASD, how immune cells interact with brain development and behavior in genetically predisposed individuals has remained unclear.

To address this, the present study used a mouse model carrying a duplication of chromosome 15q11-13 (15q dup mice), which mimics a chromosomal abnormality associated with human ASD, to investigate which immune cells are present in the developing brain. The results revealed that specific immune cells accumulate in the brain and contribute to social behavioral abnormalities via inflammatory mediators. This study provides a new perspective on ASD—not merely as a problem of brain neurons, but as a condition involving interactions between the brain and immune cells.

[Research Findings]

The research group used 15q dup mice to examine in detail which immune cells are present in the developing brain. They discovered that γδT cells, a type of immune cell, were increased in the brains of 15q dup mice compared to control mice.

Next, they investigated why γδT cells accumulate in the brain. They found that microglia in 15q dup mice were altered and produced higher levels of a molecule called CXCL16. γδT cells express the receptor CXCR6, which responds to CXCL16, and are thus recruited to the developing brain by microglia-derived CXCL16.

Further analysis of the localization and function of γδT cells in the brain revealed that these cells accumulated around the hippocampus (※5) and produced IL-17A, a pro-inflammatory molecule. Since IL-17A can affect neurons and the brain environment, these findings suggest that abnormal immune activity during brain development may lead to changes in social behavior.

Finally, the researchers tested whether this mechanism actually contributes to ASD-like behaviors. When 15q dup mice were crossed with mice lacking Vγ6-positive γδT cells, their social behavioral abnormalities improved. Moreover, when the functions of CXCL16, Vγ6-positive γδT cells, or IL-17A were blocked using antibodies, the accumulation of γδT cells in the brain and the effects of IL-17A were suppressed, and the social behavioral deficits in 15q dup mice were ameliorated. These results demonstrate a novel mechanism underlying ASD that involves brain-immune interactions, rather than neuronal dysfunction alone.

[Future Directions]

This study is a basic research project using a mouse model, and further validation is required to determine whether this mechanism applies to human ASD. Future studies will examine human ASD patient samples and datasets to investigate whether immune signals related to γδT cells, IL-17A, and CXCL16 are altered in humans.

This finding offers a new perspective on understanding ASD through brain-immune interactions. It holds promise for future development of diagnostic aids based on immune status, as well as novel therapeutic and preventive strategies.

[Glossary]

(※1) CXCL16

A chemokine protein that attracts specific immune cells.

(※2) IL-17A

Interleukin-17A, a cytokine produced by immune cells that promotes inflammatory responses. It has been implicated in autism.

(※3) γδT cells

A subset of T cells expressing a distinct γδ T-cell receptor, involved in infection defense and inflammatory responses.

(※4) Microglia

Immune cells residing in the brain and spinal cord. They remove unnecessary cells and substances, maintain the neuronal environment, and contribute to brain development and neural circuit formation.

(※5) Hippocampus

A brain region critical for memory and learning. It is also involved in social behavior, thought to play a role in remembering others and regulating social interactions through specific neural circuits.

[Acknowledgments]

This study was supported by the Ministry of Education, Culture, Sports, Science and Technology's Joint Usage/Research Center Program, the High-Depth Omics Medical Research Center at the Research Institute for Microbial Diseases, Osaka University, and CURE (JPMXP1323015486). Additional support was provided by JSPS KAKENHI grants (JP21H02719, JP21H00432, JP21H05044, JP21K19382, JP22H05061, JP23H04785, JP24K02264, JP24K22058, JP25H01865: Minako Ito; JP23H04173, JP24K02386: Manabu Makinodan), the Moonshot Research and Development Program (21zf0127003, 26zf0127012h: Minako Ito; JPMJMS239F-1-2: Manabu Makinodan), AMED-PRIME (JP22gm6210012: Minako Ito), AMED (JP21wm0425011: Minako Ito, Toru Takumi, Manabu Makinodan; 24gm1510009s0103, 24gm1910004h0002: Manabu Makinodan), AMED-CREST (22gm1510009h0001, 24gm1910004s0402: Manabu Makinodan), AMED-Brain/MINDS2.0 (JP24wm0625510: Minako Ito), JST (JP21470411: Minako Ito), and grants from the Chemo-Sero-Therapeutic Research Institute, Senri Life Science Foundation, Mitsubishi Foundation, Uehara Memorial Foundation, Inamori Foundation, and Sankyo Kagaku Kenkyujo (Minako Ito).

[Publication Information]

Journal: Science Immunology

Title: CXCL16-mediated recruitment of γδ T cells to the brain reduces sociability in mice

Authors: Natsumi Takayama, Koyomi Shiraishi, Ako Matsui, Shinya Hatano, Kazuhiko Yamamuro, Kenta Nitahara, Akira Makino, Tatsuya Yokota, Nesta Amagiri, Mahiro Watanabe, Ayame Nagafuchi, Mio Kawazoe, Minami Serino, Yoshihiro Harada, Tomoaki Takao, Kakeru Takenobu, Yasunobu Yoshikai, Kazufumi Kunimura, Manabu Makinodan, Toru Takumi, Minako Ito

DOI: 10.1126/sciimmunol.adz8466

[Contact]

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