Leptin is an adipose-secreted hormone that plays an important role in both metabolism and immunity. Leptin has been shown to induce Th1 polarization and inhibit Th2 responses. Additionally, leptin induces Th17 responses, inhibits regulatory T (Treg) cells and modulates autoimmune diseases. Here, we investigated whether leptin mediates its activity on T cells by influencing dendritic cells (DCs) to promote Th17 and Treg cell immune responses in mice. We observed that leptin deficiency: i) reduced the expression of DC maturation markers, ii) decreased DC production of IL-12, TNF-α and IL-6, iii) increased DC production of TGF-β, and iv) limited the capacity of DCs to induce syngeneic CD4(+) T-cell proliferation. As a consequence of this unique phenotype, DCs generated under leptin-free conditions induced Treg or TH 17 cells more efficiently than DCs generated in the presence of leptin. These data indicate important roles for leptin in DC homeostasis and the initiation and maintenance of inflammatory and regulatory immune responses by DCs. This article is protected by copyright. All rights reserved.