The Immune-Modulatory Properties of iPSC-Derived Antigen-Presenting Cells

Abstract

Antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages, are important regulators of the immune system, as they connect the innate and adaptive immunity by critically regulating T-cell responses. Thus, APCs are involved in both tissue homeostasis and tolerance, but also coordinate immune responses in case of infection and inflammation. Primary APCs are commonly generated from peripheral blood-derived monocytes and have been used as cell therapeutics in several (pre-)clinical settings, e.g., immune oncology, however, with varying efficiency. One promising alternative to study antigen presentation in vitro and to develop novel cell-based therapies are induced pluripotent stem cells (iPSCs). IPSCs can nowadays be generated from a variety of different cell types using several refined reprogramming techniques. Given their unlimited proliferation and differentiation potential, they hold great promise for regenerative medicine, and recently, first iPSC derivatives have found their way into first clinical studies for cell-based therapies. In this review article, we will give a brief overview of current methods for the generation and applications of primary APCs, but also specifically focus on different strategies for the generation of defined subsets of DCs and macrophages from human PSCs. Moreover, we will highlight the potential but also hurdles for the clinical translation of iPSC-derived APCs.

Keywords: Antigen presentation; Cell therapy; Dendritic cells; Induced pluripotent stem cells; Macrophage.

Fig. 1

Potential of induced pluripotent stem cells (iPSC)-derived antigen-presenting cells (APCs) for in vitro modeling of T-cell interactions. Left: Generation of iPSC-derived APCs: iPSC can be generated from easily assessable donor material, such as skin biopsies or blood samples, by overexpression of specific transcription factors. iPSC can be differentiated in vitro into different APCs, such as dendritic cells or macrophages, using specific lineage instructive cytokines (e.g., IL-4 and GM-CSF or IL-3 and M-CSF, respectively). Right: Modeling antigen presentation in vitro: Subsequently, co-cultivation of the iPSC-derived APCs with autologous or allogeneic T cells derived from peripheral blood or iPSCs can be performed to study antigen presentation in vitro (created with BioRender.com).