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Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression

Abstract

Nutritional deprivation suppresses immune function1,2,3. The cloning of the obese gene and identification of its protein product leptin4 has provided fundamental insight into the hypothalamic regulation of body weight5,6. Circulating levels of this adipocyte-derived hormone are proportional to fat mass6,7 but may be lowered rapidly by fasting8,9 or increased by inflammatory mediators10,11. The impaired T-cell immunity of mice12,13 now known to be defective in leptin (ob/ob)4 or its receptor (db/db)14,15, has never been explained. Impaired cell-mediated immunity1,2,3 and reduced levels of leptin7 are both features of low body weight in humans. Indeed, malnutrition predisposes to death from infectious diseases16. 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.

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Figure 1: Leptin enhances the alloproliferative response.
Figure 2: The long isoform of the leptin receptor is expressed in CD4+ T cells.
Figure 3: Leptin differentially affects the proliferative responses of naive and memory T cells.
Figure 4: Leptin favours the production of proinflammatory cytokines.
Figure 5: Leptin reverses starvation-induced immunosuppression.

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Acknowledgements

We thank C. Campagnoli, J. G. Chai, A. Di Giacomo, J. Gardiner, G. Lombardi, A.Macrae and L.-Q. Gao for technical assistance and for helpful suggestions and D. Gray, H. Reiser and D. Smith for critically reviewing the manuscript. G.M.L., J.K.H. and R.J.B. are MRC Clinical Training Fellows.

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Correspondence to Robert I. Lechler.

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Lord, G., Matarese, G., Howard, J. et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394, 897–901 (1998). https://doi.org/10.1038/29795

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