Hibernation is an energy-conserving behavior consisting of periods of inhibited metabolism ('torpor') with lowered body temperature. Torpor bouts are interspersed by arousal periods, in which metabolism increases and body temperature returns to euthermia. In deep torpor, the body temperature typically decreases to 2-10°C, and major physiological and immunological changes occur. One of these alterations constitutes an almost complete depletion of circulating lymphocytes that is reversed rapidly upon arousal. Here we show that torpor induces the storage of lymphocytes in secondary lymphoid organs in response to a temperature-dependent drop in plasma levels of sphingosine-1-phosphate (S1P). Regulation of lymphocyte numbers was mediated through the type 1 S1P receptor (S1P 1 ), because administration of a specific antagonist (W146) during torpor (in a Syrian hamster at ∼8°C) precluded restoration of lymphocyte numbers upon subsequent arousal. Furthermore, S1P release from erythrocytes via ATP-binding cassette (ABC)-transporters was significantly inhibited at low body temperature (4°C) but was restored upon rewarming. Reversible lymphopenia also was observed during daily torpor (in a Djungarian hamster at ± 25°C), during forced hypothermia in anesthetized (summer-active) hamsters (at ± 9°C), and in a nonhibernator (rat at ∼19°C). Our results demonstrate that lymphopenia during hibernation in small mammals is driven by body temperature, via altered plasma S1P levels. S1P is recognized as an important bioactive lipid involved in regulating several other physiological processes as well and may be an important factor regulating additional physiological processes in hibernation as well as in mediating the effects of therapeutic hypothermia in patients.ibernation is an energy-conserving behavior consisting of periods of significantly inhibited metabolism (torpor) that result in a largely reduced heart and ventilation rate (1-3) and body temperature. Torpor bouts are interspersed by arousal periods with durations of 8-24 h, during which metabolism increases and body temperature rapidly returns to euthermia (2, 4). Hibernating mammals display major changes in their physiology that lead (among other changes) to an increased resistance to ischemia/reperfusion (5, 6) and a reduced immune function (7). Remarkably, despite the repetitive cycles of cooling and rewarming, hibernating animals do not show gross signs of organ damage (8). In humans, therapeutic hypothermia is used frequently to limit neuronal injury in cardiac arrest and major surgery of brain and heart (9). However, hypothermia as used during cardiac surgery is associated with increased renal injury postoperatively (10). Therefore, unraveling the mechanisms underlying the changes in physiology of hibernating mammals might be of substantial clinical relevance.