Persistence of dysfunctional natural killer cells in adults with high-functioning autism spectrum disorders: stigma/consequence of unresolved early infectious events?

Background: Autism spectrum disorders (ASD) are characterized by abnormal neurodevelopment, genetic, and environmental risk factors, as well as immune dysfunctions. Several lines of evidence suggest alterations in innate immune responses in children with ASD. To address this question in adults with high-functioning ASD (hf-ASD), we sought to investigate the role of natural killer (NK) cells in the persistence of ASD. Methods: NK cells from 35 adults with hf-ASD were compared to that of 35 healthy controls (HC), selected for the absence of any immune dysfunctions, at different time-points, and over a 2-year follow-up period for four patients. The phenotype and polyfunctional capacities of NK cells were explored according to infectious stigma and clinical parameters (IQ, social, and communication scores). Results: As compared to HC, NK cells from patients with hf-ASD showed a high level of cell activation (p < 0.0001), spontaneous degranulation (p < 0.0001), and interferon-gamma production (p = 0.0004), whereas they were exhausted after in vitro stimulations (p = 0.0006). These data yielded a specific HLA-DR+KIR2DL1+NKG2C+ NK-cell signature. Significant overexpression of NKG2C in hf-ASD patients (p = 0.0005), indicative of viral infections, was inversely correlated with the NKp46 receptor level (r = - 0.67; p < 0.0001), regardless of the IgG status of tested pathogens. Multivariate linear regression analysis also revealed that expression of the late-activating HLA-DR marker was both associated with structural language (r = 0.48; p = 0.007) and social awareness (r = 0.60; p = 0.0007) scores in adult patients with hf-ASD, while KIR2DL1 expression correlated with IQ scores (p = 0.0083). Conclusions: This study demonstrates that adults with hf-ASD have specific NK-cell profile. Presence of NKG2C overexpression together with high-level activation of NK cells suggest an association with underlying pathogens, a hypothesis warranting further exploration in future studies.