Nutritional deprivation suppresses immune function^,,. The cloning of the obese gene and identification of its protein product leptin has provided fundamental insight into the hypothalamic regulation of body weight,. Circulating levels of this adipocyte-derived hormone are proportional to fat mass, but may be lowered rapidly by fasting, or increased by inflammatory mediators,. The impaired T-cell immunity of mice, now known to be defective in leptin (ob/ob) or its receptor (db/db),, has never been explained. Impaired cell-mediated immunity^,, and reduced levels of leptin are both features of low body weight in humans. Indeed, malnutrition predisposes to death from infectious diseases. We report here that leptin has a specific effect on T-lymphocyte responses, differentially regulating the proliferation of naive and memory T cells. Leptin increased Th1 and suppressed Th2 cytokine production. Administration of leptin to mice reversed the immunosuppressive effects of acute starvation. Our findings suggest a new role for leptin in linking nutritional status to cognate cellular immune function, and provide a molecular mechanism to account for the immune dysfunction observed in starvation.