T cells contribute to approaching positive but potentially risky stimuli through medial prefrontal cortex immune...

Avoidance behaviour, a core feature of the "Behavioural Immune System," minimizes exposure to pathogens but limits social and environmental engagement. For some individuals, the benefits of approaching attractive but risky stimuli may outweigh the costs of avoiding them. In spontaneously approaching (AP) mice, we identified the neuronal and immune correlates that contribute to individual differences in approach to positive yet potentially risky stimuli. AP mice displayed enhanced excitatory synaptic transmission and excitability in the pyramidal neurons of the medial prefrontal cortex (mPFC), a neuronal transcriptomic profile enriched for immune pathways, and an increased abundance of T lymphocytes in both the mPFC and peripheral blood. Microglia in AP mice exhibited a pro-inflammatory shift with reduced anti-inflammatory markers. Modulating lymphocyte trafficking with fingolimod abolished the approach phenotype and reduced cerebral T cells, whereas microglial inhibition with minocycline did not affect approach behaviour. These findings reveal that T-cell-associated immune modulation plays a critical role to maintain risk-oriented approach behaviour, suggesting a functional coupling between adaptive immunity and prefrontal circuits. We propose an "Approaching Immune System" that complements the classical Behavioural Immune System in regulating the flexibility of approach-avoidance behaviours. The findings provide ground-breaking insight into neuronal and immune circuits orchestrating adaptive behaviours, offering broad translational relevance for psychiatric, infectious, and chronic inflammatory disorders.