Obesity elicits an immune response characterized by myeloid cell recruitment to key metabolic organs, including adipose tissue. However, the response of immune cells to nonpathologic metabolic stimuli has been less well studied, and the factors that regulate the metabolic-dependent accumulation of immune cells are incompletely understood. Here we characterized the response of adipose tissue macrophages (ATMs) to weight loss and fasting in mice and identified a role for lipolysis in ATM recruitment and accumulation. We found that the immune response to weight loss was dynamic; caloric restriction of high-fat diet-fed mice led to an initial increase in ATM recruitment, whereas ATM content decreased following an extended period of weight loss.

While previous studies have described CD25 expression on mature dendritic cells (mDCs) and their production of IL-2, it remains unclear how these molecules participate in the activation of T cells. In search of the mechanisms by which daclizumab, a humanized monoclonal antibody against CD25, inhibits brain inflammation in multiple sclerosis (MS), we observed that while the drug has limited effect on polyclonal T cell activation, it potently inhibits activation of antigen (Ag)-specific T cells by mDCs. We demonstrate that in an Ag-specific manner, mDCs (and Ag-experienced T cells) secrete IL-2 to the mDC-T cell interface and mDCs “lend” their CD25 to primed T cells in trans, in order to facilitate early high affinity IL-2 signaling, which is critical for subsequent T cell expansion and development of Ag-specific effectors. Our data reveal a novel mechanism for the IL-2 receptor system in DC-mediated activation of T cells.

Daclizumab, an antibody against the IL-2Rα chain, inhibits brain inflammation in MS patients, while expanding CD56bright immunoregulatory NK cells in vivo. We hypothesized that this unexpected expansion is paradoxically IL-2 driven; caused by the increased availability of T-cell derived IL-2 for NK cell signaling. To this end we performed ex vivo functional analyses of CD56bright NK cells and T cells from patients in clinical trials with daclizumab. We developed in vitro models to investigate mechanisms for ex vivo observations. We observed that daclizumab treatment caused decreased numbers and proliferation of FoxP3+ Tregs, a model T cell population known to be dependent on IL-2 for proliferation and survival. As anticipated, daclizumab therapy inhibited IL-2 signaling in all T cells; however we also observed functional adaptation of T cells to low IL-2 signal in vivo, characterized by the concomitant enhancement of IL-7 signaling on all T cells and parallel increase of CD127 expression by Tregs. In contrast, IL-2 signaling on CD56bright NK cells was not inhibited by daclizumab and their in vivo proliferation and cytotoxicity actually increased. Mechanistic studies indicated that the activation of CD56bright NK cells was likely IL-2 driven, as low doses of IL-2, but not IL-15, mimicked this activation in vitro. Our study provides insight into the role that IL-2 and CD25 play in functional regulation of two important immunoregulatory cell populations in humans: FoxP3+ T regs and CD56bright NK cells.