Immune Alterations in CD8+ T Cells Are Associated with Neuronal C-C and C-X-C Chemokine Receptor Regulation Through Adenosine A2A Receptor Signaling in a BTBR T+ Itpr3tf/J Autistic Mouse Model.

Abstract

Associative studies on a range of neurodevelopmental disorders have identified relationships between behavioral deficits and immune system function. The BTBR T+ Itpr3tf/J (BTBR) mouse strain displays aberrant characteristics in its social behavior and immune responses, providing a significant opportunity to examine the relationship between behavior and the immune system. This study investigated the influence of adenosine A2A receptor activity on C-C and C-X-C chemokine receptors involved in autism in the BTBR mouse model. A2A receptors have previously been targeted in clinical trials by potential therapeutics with neuroprotective, immunomodulatory, and analgesic properties. In this study, we examined the effects of A2A receptor antagonist SCH5826 (SCH) and A2A receptor agonist CGS21680 (CGS) on C-C and C-X-C chemokine receptors (CCR3, CCR4, CCR5, CCR6, CCR7, CXCR3, CXCR4, and CXCR5) on splenic CD8+ T cells in the BTBR autistic mouse model. We also assessed the C-C and C-X-C chemokine receptors mRNA levels in brain tissue. Our results showed that CCR3+, CCR4+, CCR5+, CCR6+, CCR7+, CXCR3+, CXCR4+, and CXCR5+ production in splenic CD8+ T cells decreased significantly in BTBR-CGS-treated mice in comparison with that in BTBR control and BTBR-SCH-treated mice. In addition, RT-PCR analysis revealed decreased gene expression levels for C-C and C-X-C chemokine receptors in the brain tissue of BTBR-CGS-treated mice, whereas these levels were significantly increased in BTBR control and BTBR-SCH-treated mice. Our results suggest that treating BTBR mice with CGS decreases C-C and C-X-C chemokine receptor signaling and might therefore provide a unique avenue for developing future therapies for autism and neuroimmunological disorders.