iPSC-Derived Regulatory Dendritic Cells Inhibit Allograft Rejection by Generating Alloantigen-Specific Regulatory T Cells

Abstract

SummaryRegulatory dendritic cell (DCregs)-based immunotherapy is a potential therapeutic tool for transplant rejection. We generated DCregs from murine induced pluripotent stem cells (iPSCs), which could remain in a “stable immature stage” even under strong stimulation. Harnessing this characteristic, we hypothesized that iPS-DCregs worked as a negative vaccine to generate regulatory T cells (Tregs), and induced donor-specific allograft acceptance. We immunized naive CBA (H-2Kk) mice with B6 (H-2Kb) iPS-DCregs and found that Tregs (CD4+CD25+FOXP3+) significantly increased in CBA splenocytes. Moreover, immunized CBA recipients permanently accepted B6 cardiac grafts in a donor-specific pattern. We demonstrated mechanistically that donor-type iPS-DCregs triggered transforming growth factor β1 secretion, under which the donor-antigen peptides directed naive CD4+ T cells to differentiate into donor-specific FOXP3+ Tregs instead of into effector T cells in vivo. These findings highlight the potential of iPS-DCregs as a key cell therapy resource in clinical transplantation.

Directed Differentiation of Human Induced Pluripotent Stem Cells into Dendritic Cells Displaying Tolerogenic Properties and Resembling the CD141+ Subset

“…Since tolerance is, in essence, an in vivo phenomenon, the tolerogenicity of ipDCs can be determined unequivocally only from the outcome of future clinical trials. Nevertheless, in vitro correlates have been shown to have predictive value, especially in mouse models in which allograft rejection has been prevented by the administration of “regulatory” DCs differentiated from iPSCs ( 54 , 55 ). In these studies, the administered DCs showed decreased capacity for effector T cell priming in vitro and polarization of responding T cells toward a Treg phenotype.…”

Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation

“…The metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) overexpression promotes DC-SIGN expression by functioning as an miR155-5p sponge in the DC cytoplasm, which derives DC to Tol-DC with low expression of costimulatory molecules and high IL-10 secretion, protecting mice from acute rejection after cardiac transplantation ( 71 ). Apart from these, some biological interventions have also been used to induce Tol-DC, such as mesenchymal stem cells (MSCs) ( 72 ), induced pluripotent stem cells (iPSCs) ( 73 ), and recombinant Schistosoma mansoni antigens ( 32 ). Cai et al generated Tol-DC from murine iPSCs and injected these Tol-DC 7 days before transplantation into the recipients, resulting in a decreased expression of perforin/granzyme B, increased secretion of TGF-β, and proliferation of CTLA4 + GITR + Treg in mice with prolonged cardiac graft survival ( 73 ).…”

“…Apart from these, some biological interventions have also been used to induce Tol-DC, such as mesenchymal stem cells (MSCs) ( 72 ), induced pluripotent stem cells (iPSCs) ( 73 ), and recombinant Schistosoma mansoni antigens ( 32 ). Cai et al generated Tol-DC from murine iPSCs and injected these Tol-DC 7 days before transplantation into the recipients, resulting in a decreased expression of perforin/granzyme B, increased secretion of TGF-β, and proliferation of CTLA4 + GITR + Treg in mice with prolonged cardiac graft survival ( 73 ).…”

Acute Myeloid Leukemia Cells Express ICOS Ligand to Promote the Expansion of Regulatory T Cells

“…Tregs comprise natural and inducible Tregs, and usually express CD25, glucocorticoid-induced TNFR-related protein (GITR), cytotoxic T lymphocyte associated antigen 4 (CTLA-4) and CD45RO, and lack CD127 ( 3 ). Tregs can suppress the proliferation and cytokine secretion of responding effector T cells (Teffs) to prevent autoimmune diseases, allergies, infection-induced organ pathology as well as transplant rejection ( 4 , 5 ). However, Tregs can be deleterious in cancer through suppression of anti-tumor immunity ( 6 ).…”