Differentiation of Dendritic Cells from Human Induced Pluripotent Stem Cells

Abstract

Dendritic cells (DCs) occupy a pivotal role in the immune system bydetermining the outcome of antigen presentation, either elicitingan aggressive immune response or imposing a state of immunologicaltolerance. As such, DCs serve as an obvious point of interventionfor therapeutic purposes: while targeting DCs to enhance the responseto tumour associated antigens (TAAs) remains the goal of cancer immunotherapy,reducing deleterious immune responses is critical for the treatmentof autoimmunity and allograft rejection, or in situations in whichtherapeutic proteins may prove immunogenic upon administration. Functionalheterogeneity among DCs suggests that distinct subsets may provesuitable for different applications. In terms of cancer vaccination,for example, much interest has focused on the recently-describedsubpopulation of CD141+XCR1+ DCs, capable of cross-presenting exogenousantigens in an MHC class I-restricted manner, since these may recruitcytotoxic T cells to the eradication of transformed cells. Furthermore,conventional DCs may be rendered pro-tolerogenic upon exposure tovarious pharmacological agents such as rapamycin and interleukin10 (IL-10). For all such applications, a well-defined source of patient-derivedDCs is highly desirable which is tractable for in vitro culture,expansion and manipulation. Given that for many disease states amenableto such strategies for therapeutic intervention, use of the patient’sown peripheral blood is contraindicated, we have investigated theuse of autologous induced pluripotent stem cells (iPSCs) as an alternativesource of DCs. Here we describe our recently-published protocolsfor the derivation of DCs from human iPSCs that yield around 90–95%CD11c+ DCs, of which up to 40% express the CD141+XCR1+ phenotypeof the subset capable of antigen cross-presentation. These protocolstherefore form a promising foundation for the future clinical applicationof DCs to immunotherapy.