Abstract
The curative potential of non-autologous cellular therapy is hindered by the requirement of anti-rejection therapy. Cellular encapsulation within nondegradable biomaterials has the potential to inhibit immune rejection, but the efficacy of this approach in robust preclinical and clinical models remains poor. While the responses of innate immune cells to the encapsulating material have been characterized, little attention has been paid to the contributions of adaptive immunity in encapsulated graft destabilization. Avoiding the limitations of animal models, we established an efficient, antigen-specific in vitro platform capable of delineating direct and indirect host T cell recognition to microencapsulated cellular grafts and evaluated their consequential impacts. Using ovalbumin (OVA) as a model antigen, we determined that alginate microencapsulation abrogates direct CD8+ T cell activation by interrupting donor-host interaction; however, indirect T cell activation, mediated by host antigen presenting cells (APCs) primed with shed donor antigens, still occurs. These activated T cells imparted cytotoxicity on the encapsulated cells, likely via diffusion of cytotoxic solutes. Overall, this platform delivers unique mechanistic insight into the impacts of hydrogel encapsulation on host adaptive immune responses, comprehensively addressing a long-standing hypothesis of the field. Furthermore, it provides an efficient benchtop screening tool for the investigation of new encapsulation methods and/or synergistic immunomodulatory agents.
•An efficient benchtop model capable of characterizing adaptive immune responses to encapsulated cells was developed.•The platform determined that encapsulated cells/organoids activate host T cells via an APCs-mediated indirect recognition pathway.•The amount and density of the encapsulated cells direct the magnitude of indirect T cell activation.•The resulting T effector cells were cytotoxic to the encaged organoids across the biomaterial barrier.•This benchtop platform could be used in future studies to screen immune interventions for therapeutic applications.
