One cell to rule them all: Immune regulation of the brain in autism spectrum disorder

Abstract

Autism spectrum disorders (ASD) is a neurodevelopmental disorder characterized by impaired social, behavioral, and cognitive development with current prevalence rates of 1 in 36 children in the United States. The underlying etiology of ASD is complex, and epidemiological studies suggesting a role for both genetic and environmental contributions. Possible immune links with ASD have been postulated ever since the first description by Kanner over 80 years ago. Unlike viral encephalitis or autoimmune diseases such as multiple sclerosis, there are no mass increases of immune cells in the brain causing prominent tissue damage. Thus, in the absence of evidence for overt acute and chronic inflammation in the brains of individuals with ASD many investigators have turned to other cells and molecules to investigate neuroimmune interactions. These have included cells such as microglia that fit nicely into the lexicon of both neuroscientists and immunologists. Microglia the brain’s resident immune cell, constantly monitor for signs of infection and can directly sculpt neuronal connections in the developing brain by selective phagocytosis of neuronal precursor cells, the removal of newborn neurons undergoing apoptosis, the regulation of stem cell proliferation and survival of new neurons, and by modulating synapse formation and synaptic transmission. Canada et al. also highlights the role of microglia in controlling white matter development by regulating oligodendrocyte cell lineages, cytokine production, levels of neurotrophins, and growth factor release (Canada et al. 2025).

Microglia arise from the yolk sac myeloid progenitors, migrate to the brain, and colonize the neural folds during embryogenesis. Under healthy conditions, microglia actively survey their local environment and make contact with astrocytes, neuronal dendritic spines, and axon terminals. Reductions in microglia prenatally or postnatally result in increased neuronal precursor numbers, an excess of weak excitatory synapses, decreased brain functional connectivity, deficits in social interaction, and increased repetitive behaviors. Upon immune activation, microglia adopt a morphology characterized by retraction and thickening of processes and enlargement of the soma. Early human postmortem brain studies in ASD found increased microglia and astroglia activation and increased pro-inflammatory cytokine levels in multiple brain regions (Vargas et al. 2005). Further brain tissue studies showed alterations in gene expression and DNA methylation of immune related genes, M1/M2 microglia skew, increased microglia density in fronto-insular, visual and dorsolateral prefrontal cortex, and activated microglia morphology in the dorsolateral prefrontal cortex, amygdala, and cerebellum. Using positron emission tomography and a TSPO radiotracer for microglia, several groups have found evidence for increased microglia activation in multiple brain regions in young adults with Asperger's syndrome and ASD (reviewed in Hughes et al. 2023).

As discussed by Canada and colleagues, microglia play a critical role in coordinating the function of oligodendrocytes leading to increased myelination and white matter volume in ASD. So far, there is a compelling picture for abnormal microglia function in ASD pathophysiology. However, there are other immune cells in the brain that influence or direct microglia function through cell-to-cell contact and/or cytokine release. The immunological compartment of the brain consists of both tissue-resident immune cells and leukocytes recruited from the blood. This includes regulatory T cells (Tregs) a specialized subset of T cells that are anti-inflammatory, promote immune tolerance, and tissue repair. Tregs are found within the perivascular spaces, the meninges, choroid plexus/CSF, cribriform plate, and the brain parenchyma (Pasciuto et al. 2020). Tregs reduce microglial reactivity in response to a range of neurological insults, and directly assist in regenerative and reparative processes in the brain. Removal of Tregs leads to an increased microglia activation morphology with reduced arborization, fewer branches, and shorter processes, as well as increased neuronal cell death, and decreased hippocampal neurogenesis (Marin-Rodero et al. 2025). Importantly Tregs support myelin regeneration by resolving pro-inflammatory cytokine production, promoting phagocytosis, and directly signaling to oligodendrocyte progenitor cells to differentiate into myelin-producing oligodendrocytes (Dombrowski et al. 2017). Such processes deemed vital in white matter development (Canada et al. 2025). Tregs also inhibit activated IFNγ-producing T cell and NK cell infiltration into the brain parenchyma providing a means of protection against autoreactive or pathogenic cells activated in the peripheral tissues (Marin-Rodero et al. 2025).

In ASD, fewer Tregs compared to controls have been seen in the periphery and decreased numbers are associated with worse behavior and an increased burden of comorbidities. Lower levels of anti-inflammatory cytokine that are produced by various Tregs populations, such as IL-10, IL-35, and TGFβ1, have also been described in ASD. Furthermore, evidence for effector CD8+ T cells trafficking to the brain have been shown in ASD studies, possibly due to decreased Tregs numbers or function that when overwhelmed allow entry (reviewed in Moreno et al. 2025). These data suggest a shift to an inflammatory environment and increased cellular infiltration in the brain in ASD due to decreased Tregs activity. Furthermore, for over 20 years, the maternal immune activation (MIA) animal model—that relies on an immune insult to be administered during early/midgestation—has frequently been used to model susceptibility for neurodevelopment disorders. Long-lived changes in microglial phagocytosis activity, transcription, and morphology are seen in MIA offspring. In the healthy brain, there is very little replacement of resident microglia from peripheral monocytes, however, in MIA offspring, increased monocytic infiltration was seen in the brain and associated with increased TNFα production (Chen et al. 2020). Blocking activated inflammatory immune cell egress can have positive effects on behaviors in MIA models (Butera et al. 2024). Moreover, reduced Tregs has been observed in MIA but adoptive transfer of activated Tregs rescued both MIA-induced immune and behavioral phenotypes (Xu et al. 2021). Further therapeutic strategies designed to return Tregs numbers and function to a homeostatic, baseline states may provide a valuable treatment option for reducing ASD symptoms.

Data from humans and animal models have implicated microglia as important sentinels of ASD pathogenesis and white matter development. These data also suggest that neuroinflammation may be a universal ASD phenotype independent of the underlying etiology. However, microglia may be under the influence of a more powerful master, one that casts an all-seeing eye on controlling inflammation and homeostasis in the brain. A master controller or one cell to rule them all.

Author contributions

Paul Ashwood (Conceptualization, Writing—original draft, Writing—review & editing).

Funding

We would like to acknowledge funding and support of the National Institute of Child Health and Disease (R01HD090214), National Institutes of Mental Health (R01MH118209), the Jane Botsford Johnson Foundation, Grace Gardner Johnson Foundation, and the Brain Foundation.

Conflict of interest statement: None declared.

References