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Credit: CORBIS

There is a growing understanding of how host metabolism can affect the immune system. Now, a study by Procaccini et al. has described another important link between host energy status and immune function by showing that leptin, a hormone that is mainly produced by adipocytes and that controls food intake and energy expenditure, can activate mammalian target of rapamycin (mTOR) and regulate the proliferative capacity of regulatory T (T_Reg) cells.

mTOR is a serine/threonine kinase that integrates signals from environmental nutrients and growth factors to control cell proliferation and differentiation. In initial experiments conducted in vitro, freshly isolated human T_Reg cells showed higher mTOR activity and an increased metabolic rate compared with purified effector T cells. Although T_Reg cells do not normally proliferate in response to in vitro T cell receptor (TCR) stimulation, transient inhibition of mTOR, through pretreatment with rapamycin, led to robust proliferation of T_Reg cells following culture with CD3- and CD28-specific antibodies. Extending these findings in vivo, the authors found that a single injection of rapamycin promoted T_Reg cell proliferation in mice, both in the steady state and after immunization with antigen. Additionally, in a model of experimental autoimmune encephalomyelitis (EAE), mice treated with rapamycin before EAE induction showed increased frequencies of T_Reg cells and decreased disease severity. Interestingly, although decreased mTOR activity seemed to be necessary for the initial phases of T_Reg cell proliferation, T_Reg cells that were actively proliferating in vivo expressed high levels of phosphorylated mTOR. Furthermore, continuous treatment with rapamycin or silencing of mTOR expression with short hairpin RNA failed to reverse T_Reg cell anergy in vitro. Thus, although early, transient inhibition of mTOR activity could overcome T_Reg cell anergy, subsequent upregulation of mTOR activity seemed to be required to sustain T_Reg cell proliferation, indicating that the mTOR pathway has a dynamic role in T_Reg cell responsiveness.

As previous work showed that leptin can be produced by, and inhibits the proliferation of, T_Reg cells, the authors predicted that this molecule might interact with the mTOR pathway. In support of this, addition of leptin to cultures of TCR-activated, rapamycin-treated T_Reg cells led to increased activation of the mTOR pathway and prevented T_Reg cell proliferation. In addition, neutralization of leptin markedly reduced mTOR activity in cultured T_Reg cells, suggesting that autocrine production of leptin by T_Reg cells may promote their high mTOR activity in vitro.

Finally, the authors examined the effects of acute starvation (which markedly reduces circulating levels of leptin and immune function) on the mTOR pathway and T_Reg cell function. Strikingly, starvation led to increased proportions of T_Reg cells in peripheral lymph nodes. Furthermore, T_Reg cells from starved mice showed markedly reduced mTOR activity and increased rates of proliferation in vitro compared with T_Reg cells from control animals.

Taken together, this study describes the leptin–mTOR signalling pathway as an important link between host energy status and T_Reg cell activity. The authors conclude that oscillating mTOR activity is necessary for T_Reg cell activation and suggest that this may explain why T_Reg cells are unresponsive to TCR stimulation in vitro, where high levels of leptin and nutrients may sustain mTOR activation.