Dopaminergic modulation of NK cell maturation and immune-associated social behavior in a 15q dup mouse model

Autism spectrum disorder (ASD) is a neurodevelopmental condition frequently associated with immune dysregulation, yet the mechanistic basis of this comorbidity remains poorly understood. Using the paternal 15q11-13 duplication (15q dup) mouse model of ASD, we identify that systemic dopamine deficiency is associated with impaired terminal maturation and effector function of natural killer (NK) cells. Functionally, dopaminergic stimulation promotes NK cell maturation and activity in a D1-like receptor-cAMP associated manner, accompanied by altered expression of the NK maturation-related transcription factor Tbx21. Notably, pharmacological activation of D1-like receptors enhances anti-tumor immunity and improves social behavior in an NK-dependent manner in 15q dup mice. Together, these findings support a dopaminergic neuroimmune framework in which systemic dopamine signaling is associated with innate immune regulation and immune-dependent behavioral phenotypes in the 15q dup mice.