It is well established that dendritic cells (DCs) 2 play a key role as professional antigen-presenting cells in initiating and coordinating antigen-specific adaptive immunity (1, 2). By constitutively sampling the external microenvironment through receptor-mediated and non-receptor mediated endocytic pathways, DCs initiate, program, and regulate the effector response against a variety of antigens (3-7). Although much is known about the immunobiology of DC antigen processing and presentation and the effect of different cytokines on DC maturation and their subsequent effect on the immune response (8), little is known about how the configuration or geometry of cytokine transmission affects the DC response. For example, physiologically, although IL-2 and IL-15 belong to the same four a-helix family of cytokines, IL-2 is transmitted as a soluble paracrine or autocrine factor (9, 10), whereas IL-15 is trans-presented on the surface of DCs and other cell types through a stable complex (11) with IL-15R␣ (12, 13) or secreted as a soluble paracrine complex (14, 15). The quality and manner by which cytokines are delivered to DCs can have a profound effect on the subsequent effector immune response (16,17).Nanosystems such as nanoparticles (18,19), nanotubes (20), or even macromolecular systems (21) comprise an emerging strategy for controlling antigen and cytokine transmission to . Perhaps one of the most explored carriers has been the polymeric poly(lactide-co-glycolide) (PLGA) system because of its significant promise and established effect in clinical settings (25-27) and well understood methods of formulation for delivery of small-molecule drugs, nucleic acids, and protein antigens (22, 28 -31). Several studies have demonstrated the promise of antigen-loaded PLGA nanoparticles as nanoparticle-based vaccines and delivery systems targeting DCs (32-39).IL-15 is a homeostatic cytokine for CD8 ϩ T cells and natural killer cells and an important regulator of the cytotoxic immune response (40). IL-15 signals by binding to cells expressing the IL-2/IL-15 /␥ receptor and is found complexed to . This IL-15:IL-15R␣ complex is termed heterodimeric . IL-15R␣ is expressed by several cell types in * C. B. and G. N. P. are inventors on United States Government-owned patents and patent applications related to heterodimeric IL-15 and gene expression optimization. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.