Leptin-induced mTOR activation defines a specific molecular and transcriptional signature controlling CD4+ effector T cell responses.
The sensing by T cells of metabolic and energetic changes in the microenvironment can determine the differentiation, maturation, and activation of these cells. Although it is known that mammalian target of rapamycin (mTOR) gauges nutritonal and energetic signals in the extracellular milieu, it is not known how mTOR and metabolism influence CD4+CD25-FOXP3- effector T cell (Teff) responses. In this article, we show that leptin-induced activation of mTOR, which, in turn, controls leptin production and signaling, causes a defined cellular, biochemical, and transcriptional signature that determine the outcome of Teff responses, both in vitro and in vivo. The blockade of leptin/leptin receptor signaling, induced by genetic means or by starvation, leads to impaired mTOR activity that inhibits the proliferation of Teffs in vivo. Notably, the transcriptional signature of Teffs in the presence of leptin blockade appears similar to that observed in rapamycin-treated Teffs. These results identify a novel link between nutritional status and Teff responses through the leptin-mTOR axis and define a potential target for Teff modulation in normal and pathologic conditions.
Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Napoli 80131, Italy.
Claudio
C
Procaccini
Veronica
V
De Rosa
Mario
M
Galgani
Fortunata
F
Carbone
Silvana
S
Cassano
Dario
D
Greco
Kui
K
Qian
Petri
P
Auvinen
Gaetano
G
Calì
Giovanni
G
Stallone
Luigi
L
Formisano
Antonio
A
La Cava
Giuseppe
G
Matarese
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D020738:Leptin / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008822:Mice, Transgenic; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology*
D020738:Leptin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus