Leptin-dependent regulation of immune homeostasis and function. In a naïve CD4⁺ T cell, the LEPR-dependent intracellular signaling enhances the differentiation toward pro-inflammatory Th1/Th17 cells while inhibiting the proliferation of FOXP3⁺ T reg cells. Furthermore, at absent/low levels of leptin the growth and function of Th1/Th17 is impaired, while T reg cells expand more efficiently and release more regulatory-type cytokines. The opposite occurs when leptin levels are aberrantly high and enhance Th1/Th17 differentiation and growth on one side and inhibit T reg cell proliferation on the other. This different cellular response to leptin depends on the different sensitivity of Th1/Th17 and T reg cells to either physiologically fluctuating LEPR-mTOR activation (low/normal leptin) or consistent hyperstimulation of the same pathway (high leptin). The two opposite situations are correlated with either higher susceptibility to infections (low leptin: effector arm inefficient, elevated immune suppression) or enhanced susceptibility to autoimmunity (high leptin: effector arm hyperactive, inefficient immune regulation). Schematic figures were created with images adapted from Smart Servier Medical Art (http://www.servier.fr/servier-medical-art). P, phosphorylated.