Vagal nerve activity as a moderator of brain–immune relationships

•Vagal tone indexed by heart rate variability reflects biological regulatory capacity.•Vagal tone is linked with flexible immune and physiological stress responses.•Frontal-striatal network mediates effects of vagal tone on stress responses.

We investigated whether vagal tone, as assessed by heart rate variability (HRV), moderates the neural correlates of immune and physiological responses to acute stress. Participants with low and high baseline HRV underwent a reversal learning task as an acute stressor. Natural killer cells, norepinephrine, and adrenocorticotropic hormone in peripheral blood changed with acute stress in the high HRV group only. Activity in the prefrontal cortex and striatum correlated with the immune and physiological indices in the high HRV group. High vagal tone may reflect more flexible top-down brain regulation of immune and physiological activity.