A Comprehensive Platform for T-Cell Stimulation Based on Biodegradable Polymeric Artificial Antigen-Presenting Cells

Artificial antigen-presenting cells (aAPCs) are synthetic particles that mimic the action of professional antigen-presenting cells during interactions with T cells. aAPCs offer advantages over the use of live cells to stimulate T cells in vitro; however, current aAPC systems lack one or more of the three necessary signals for physiological T-cell stimulation: recognition, costimulation, and soluble cytokine signals. We incorporated these signals in a biodegradable aAPC constructed from poly(lactide-co-glycolide), a safe polymer with established use in humans. Our aAPCs present a high density of adaptor elements for attaching recognition and costimulatory ligands to a biodegradable core encapsulating the cytokine interleukin-2 (IL-2). Sustained release of IL-2 from aAPCs simulates a physiologic paracrine mode of IL-2 delivery and dramatically improves the stimulatory capacity of this system compared to bulk addition of cytokine.;We demonstrate that biodegradable aAPCs are capable of delivering all three essential signals to T cells, resulting in a 45-fold expansion of murine T cells after four days. Controlled release of IL-2 from aAPCs delivering nanogram quantities of IL-2 increases the potency of the cytokine by more than 1000-fold by creating and maintaining high local concentrations in the vicinity of T cells. Varying spatiotemporal aspects of IL-2 delivery revealed that paracrine IL-2 delivery signals CD8+ T cells to proliferate but results in CD4+ T-cell apoptosis due to activation-induced cell death. The effects of paracrine IL-2 aAPCs depend on nanometer-scale contact between T cells and aAPCs and continued release of picogram levels of IL-2. Furthermore, aAPC diameter is an important parameter dictating the potency of aAPCs; micro-scale aAPCs are 50% more potent than nano-scale aAPCs.;The aAPC developed in this thesis is the first platform to delivering sustained and controlled cytokine signals with T cell recognition and costimulation, and its use revealed intrinsic differences in the response of CD4+ and CD8+ T cells to paracrine IL-2 delivery. This finding has implications for understanding T cell communication in vivo and for the design of T cell-targeted therapeutics.