CD8+ T Cell Activation in Children with Autism

Background: Alterations in genes controlling immune responses as well as changes in dynamic cell function have been noted in children with autism. It has long been known that extensive interactions occur between the immune system and neuronal system/brain, and that normal neurodevelopment is contingent upon an appropriate interaction with the immune system. In model systems, it has been shown that abnormal immune function can detrimentally influence early brain development. CD8+ T cells are important in the prevention of infections, the eradication of pathogens and in controlling immune responses. Previous transcriptome studies implicated abnormal expression of genes predominantly expressed by CD8+ T cells in autism, but as yet little to no functional data has been described for these cells. We hypothesized that children with autism have a fundamental defect at the CD8+ T cells immune cell level that leads to abnormalities in immune function noted in many children with autism.

Objectives: Based on our previous reports of gene expression in autism and altered immune cell function, we sought to establish whether CD8+ T cells have abnormal phenotypes and function in autism.

Methods: Peripheral blood mononuclear cells (PBMC) from 16 children with autism and 16 typically developing children between the ages of 2 and 5 years were obtained by density gradient centrifugation. Dynamic cell function was determined by stimulation of PBMC with PMA/ionomycin for 24 hours. Supernatants were collected and analyzed for cytokine production by luminex analysis. Phenotypic analysis of CD8+ T cells were performed by flow cytometry.

Results: The percent of CD8+ T cells that contained the cytolytic proteins, perforin and granzyme B  were increased in unstimulated cell cultures from children with autism compared to controls (p < 0.004). Following stimulation the number of CD8+ T cells containing cytolytic proteins increased significantly in controls but decreased in children with autism (p < 0.01). In addition, following stimulation, surface expression of CD107a, a marker of granule release, was decreased in children with autism compared to controls (p <0.003), suggesting that activation and release of cytolytic proteins due to stimulation was altered in autism compared to controls. Intracellular staining of the inflammatory cytokine interleukin-6 (IL-6) in CD8+ T cells was increased at resting levels in children with autism compared to controls (p = 0.03). However, following stimulation intracellular IL-6 and interferon gamma (IFNg) were increased significantly in controls but decreased in children with autism (p < 0.01), possibly suggesting an “exhausted” or “maximized” cellular response.

Conclusions: These studies point to specific CD8+ T cell function abnormalities in the blood of individuals with autism. Abnormal CD8+ T cell function may represent an important link between inflammatory processes that have reported in some children with autism, and could point to a specific immune basis for the disorder in many subjects.