Dysregulation of T cell immunoglobulin and mucin domain 3 (TIM-3) signaling in peripheral immune cells is associated with immune dysfunction in autistic children

Abstract

Evidence suggests that immune dysregulation is associated with autism spectrum disorder (ASD). T cell immunoglobulin and mucin domain-3 (TIM-3) has a critical role in several inflammatory disorders; however, the role of TIM-3 signaling has not been demonstrated in ASD. In the present study, we assessed the role of TIM-3 signaling in children with ASD. We expected that increased numbers of TIM-3⁺ cells could alter immune function in children with ASD. We revealed production of TIM-3 on CD3⁺, CD4⁺, CD8⁺, CD11a⁺,b⁺, CD14⁺, CD62P⁺, and CXCR5⁺ PBMCs in children with ASD and typically developing (TD) controls using immunofluorescent staining. We further demonstrated the production of IL-1β, IFN-γ, IL-17 A, and Foxp3 in TIM-3⁺ PBMCs of TD controls and individuals with ASD. We also observed the mRNA expression levels of TIM-3, CD11a,b, CD14, IL-1β and IFN-γ using RT-PCR. We further assessed the protein levels of TIM-3, IL-1β, CXCR5, and IFN-γ using western blotting. The results showed that children with ASD had increased numbers of CD3⁺TIM-3⁺, CD4⁺TIM-3⁺, CD8⁺TIM-3⁺, CD11a,b⁺TIM-3⁺, CD14⁺TIM-3⁺, CD62P⁺TIM-3⁺ and CXCR5⁺TIM-3⁺ cells compared with TD controls. Our results further showed that children with ASD had increased IL-1β⁺TIM-3⁺, IFN-γ⁺TIM-3⁺, and IL-17⁺TIM-3⁺, and decreased Foxp3⁺TIM-3⁺ production compared with that in TD controls. Our results indicated that children with ASD significantly induced TIM-3, CD11a,b, CD14, CXCR5, IL-1β and IFN-γ mRNA and protein expression levels compared with TD controls. The results suggested that detection of TIM-3 signaling could contribute to the early diagnoses of ASD.

Keywords: Autism spectrum disorder; Cell surface receptor; Cytokines; Peripheral blood mononuclear cells; T cell immunoglobulin and mucin domain-3; Typically developing controls.