Generation of Induced Pluripotent Stem Cells Derived Tolerogenic Dendritic Cells and Their Immunosuppressive Properties.

Background: Dendritic cells (DCs), the primary antigen-presenting cells, regulate immune priming. DCs with a semi-mature phenotype and tolerogenic properties, termed tolerogenic DCs (tolDCs), are promising candidates for cell therapy to induce immune tolerance. Induced pluripotent stem cells (iPSCs) can provide an unlimited source of DCs, and in mice, tolDCs can be generated from bone marrow cells by adding agents such as minocycline and dexamethasone during DC differentiation. On this basis, we aimed to establish a protocol for generating tolDCs from iPSCs. Methods: We modified an existing iPSC-to-DC induction protocol by adding minocycline and dexamethasone. Then, we assessed whether the resulting cells exhibited tolDC characteristics through comparison of iPSC-derived DCs (iPS-DCs) and iPSC-derived tolDCs (iPS-tolDCs). Results: We established a method for generating iPS-tolDCs from iPSCs. Flow cytometric analysis revealed reduced expression of co-stimulatory molecules and the maturation marker in iPS-tolDCs compared with iPS-DCs. In co-culture experiments, CD4⁺CD45RA⁺ T cells isolated from PBMCs of healthy donors or patients with autoimmune diseases showed reduced proliferation when cultured with iPS-tolDCs compared with iPS-DCs. Gene expression profiles of iPS-tolDCs differed from those of iPS-DCs. Conclusion: We developed a protocol for producing tolDCs from iPSCs and demonstrated their tolerogenic phenotype and immunosuppressive effects on T cells. These findings indicate that iPS-tolDCs are a promising candidate for cellular immunotherapy and warrant further investigation.