Two new studies from the UC Davis MIND Institute examined regulatory T cells (Tregs) and their potential role in neuroinflammation and behavioral changes associated with autism.
Tregs act as immune system "brakes," calming inflammation to prevent overreaction. They are often decreased in autistic individuals.
Previous studies have found higher levels of inflammatory immune cells in the blood, brain and gastrointestinal tissues of people with autism. These increased inflammatory responses are often linked to greater behavioral support needs, while higher levels of Tregs are associated with improved behavioral outcomes. Despite this, Tregs have not been well studied in autistic children, and their potential as a therapeutic target remains largely unexplored.
Altered Tregs in autistic children
The first study, published in the Journal of Neuroinflammation, characterized Tregs in children with autism. It determined if gastrointestinal (GI) issues, a common co-occurring condition, altered Tregs in a unique way.
The researchers found autistic children had altered Tregs both in number and in the genes those cells use. This was compared to typically developing children. All participants were enrolled in the CHARGE study (Childhood Autism Risk from Genetics and Environment), an ongoing study that supports autism research.
The researchers compared the number and type of Tregs in 36 children with autism and 18 typically developing children. They also examined gene expression in Tregs to determine if there were differences between the two groups. In addition, they looked at the relationship between Tregs and gastrointestinal symptoms in autistic children.
The researchers found children with autism showed altered Tregs. Compared to typically developing children, children with autism had:
- A lower number of Tregs. Tregs were generally reduced in autistic children but decreases in specific Treg populations differed depending on whether a child had GI issues. Children with autism and GI issues had fewer Tregs capable of producing anti-inflammatory proteins. Children without GI issues had fewer Tregs capable of dividing after activation.
- Differentially expressed genes. Tregs from autistic children had 213 differentially expressed genes, with 171 upregulated (increased output) and 42 downregulated (decreased output).
The upregulated genes mainly help cells reorganize and repair DNA and adjust how they manage energy and fat metabolism. The downregulated genes were mostly involved in energy production, such as the conversion of oxygen and nutrients into usable energy.
The researchers note that more research is needed, but that these changes in metabolism and DNA organization suggest the identity of Tregs is unstable. One commonality was that having fewer Tregs was associated with more challenging behaviors in both typically developing children and children with autism.
"These differences in Treg populations may help explain the higher levels of inflammation seen in autism and could be linked to both gastrointestinal problems and certain behavioral traits," said Rachel Moreno, a postdoctoral fellow at the MIND Institute and first author of the study. "This data further supports the idea that the immune system plays an important role in autism in at least some individuals."
Exploring Tregs as potential biological therapies
There is growing interest in biological therapies for autism that target Tregs.
In a second study, also published in the Journal of Neuroinflammation, the authors assessed whether increasing Tregs could reduce inflammation and behavioral challenges.
They used a mouse model of altered neurodevelopment, maternal immune activation (MIA), in which offspring exhibit autism-like behaviors.
The team transferred Tregs from healthy mice into male and female MIA mice, and evaluated tissues commonly inflamed in autism, including blood, brain and gut.
They found significant sex differences in the MIA mouse offspring that received the Treg transfer, with males showing greater changes than females.
These results suggest that Treg therapy could be a promising approach for reducing inflammation and related impacts in conditions linked to maternal immune activation and neurodevelopmental conditions such as autism."-Paul Ashwood, professor, Department of Medical Microbiology and Immunology and UC Davis MIND Institute
Male mice showed:
- Healthier immune balance: Treg treatment increased helpful Treg cells and reduced pro‑inflammatory cells in both the spleen and gut.
- Lower inflammation: Males produced fewer inflammatory cytokines, such as IL‑17, after treatment, indicating a calmer immune system.
- Widespread changes in the brain: Hundreds of genes in the cerebellum, frontal cortex and hippocampus changed after Treg treatment, many related to brain development, immune activity and conditions like autism.
- Improved behavior: After Treg treatment, males showed improvements in behaviors such as self-grooming and socializing.
Female mice showed:
- Smaller immune effects: Females showed fewer changes in immune cells, and Treg treatment had only a modest impact on gut and spleen cell types.
- Mixed inflammatory signals: Some inflammatory molecules decreased (like IL‑6), while others increased after treatment, suggesting a more complex response.
- Minimal changes in the brain: Females showed little to no change in brain gene expression after treatment.
- Improved social behavior: Treg treatment helped restore normal social behaviors in females, but self-grooming did not improve.
"Transferring Tregs reduced inflammation and improved brain and behavioral outcomes in the MIA model, with the most significant benefits seen in male mice," said Paul Ashwood, senior author of both studies. Ashwood is a professor in the UC Davis Department of Medical Microbiology and Immunology and a faculty member with the UC Davis MIND Institute.
"These results suggest that Treg therapy could be a promising approach for reducing inflammation and related impacts in conditions linked to maternal immune activation and neurodevelopmental conditions such as autism," Ashwood said.
Limitations of both studies
The researchers noted several limitations. The first study was limited by its small sample size. In the second study, the Treg transfer occurred at 10 weeks, and transferring into younger mice (when the immune and brain systems are still developing) may be more relevant for inflammation than for behavior modification.
Full lists of co-authors can be found in the papers.
This research was supported by the National Institute of Child Health and Human Development (R01HD090214), National Institutes of Mental Health (R01MH118209), Department of Defense (W91XWH1810681), Autism Speaks, Autism Research Institute, the Jane Botsford Johnson Foundation, Grace Gardner Johnson Foundation, the Jonty Foundation, HEDCO Foundation and The BRAIN Foundation.
