Social status affects health by influencing the capacity of the immune system to respond to infection and disease. However, the neuronal mechanisms that explain how social status causes individual differences in immunity are unknown. In this study, we observed that among social groups of four male mice, those ranked second in hierarchy display superior T-cell expansion upon vaccination. The improved T-cell responses in second ranked mice were dependent on the ability of synaptic communication in the brain. The brain circuits that control the position in the social hierarchy are beginning to emerge, with the dorsomedial prefrontal cortex (dmPFC) as a central player. We found that selectively improving the strength of dmPFC synapses or increasing the activity of dmPFC neurons is sufficient to boost antigen-specific T-cell expansion in response to vaccination. These findings reveal a causal link between the dmPFC and the peripheral immune system, enriching our understanding of the origin of health problems caused by social inequality.