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Direct reprogramming of fibroblasts into antigen-presenting dendritic cells

Rosa, Fábio F. LU ; Pires, Cristiana F. LU ; Kurochkin, Ilia; Ferreira, Alexandra G. LU ; Gomes, Andreia M.; Palma, Luís G.; Shaiv, Kritika; Solanas, Laura; Azenha, Cláudia and Papatsenko, Dmitri, et al. (2018) In Science immunology 3(30).
Abstract

Ectopic expression of transcription factors has been used to reprogram differentiated somatic cells toward pluripotency or to directly reprogram them to other somatic cell lineages. This concept has been explored in the context of regenerative medicine. Here, we set out to generate dendritic cells (DCs) capable of presenting antigens from mouse and human fibroblasts. By screening combinations of 18 transcription factors that are expressed in DCs, we have identified PU.1, IRF8, and BATF3 transcription factors as being sufficient to reprogram both mouse and human fibroblasts to induced DCs (iDCs). iDCs acquire a conventional DC type 1-like transcriptional program, with features of interferon-induced maturation. iDCs secrete inflammatory... (More)

Ectopic expression of transcription factors has been used to reprogram differentiated somatic cells toward pluripotency or to directly reprogram them to other somatic cell lineages. This concept has been explored in the context of regenerative medicine. Here, we set out to generate dendritic cells (DCs) capable of presenting antigens from mouse and human fibroblasts. By screening combinations of 18 transcription factors that are expressed in DCs, we have identified PU.1, IRF8, and BATF3 transcription factors as being sufficient to reprogram both mouse and human fibroblasts to induced DCs (iDCs). iDCs acquire a conventional DC type 1-like transcriptional program, with features of interferon-induced maturation. iDCs secrete inflammatory cytokines and have the ability to engulf, process, and present antigens to T cells. Furthermore, we demonstrate that murine iDCs generated here were able to cross-present antigens to CD8+ T cells. Our reprogramming system should facilitate better understanding of DC specification programs and serve as a platform for the development of patient-specific DCs for immunotherapy.

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@article{e55030ac-0449-4fb3-b8ca-503cbf8c6911,
  abstract     = {<p>Ectopic expression of transcription factors has been used to reprogram differentiated somatic cells toward pluripotency or to directly reprogram them to other somatic cell lineages. This concept has been explored in the context of regenerative medicine. Here, we set out to generate dendritic cells (DCs) capable of presenting antigens from mouse and human fibroblasts. By screening combinations of 18 transcription factors that are expressed in DCs, we have identified PU.1, IRF8, and BATF3 transcription factors as being sufficient to reprogram both mouse and human fibroblasts to induced DCs (iDCs). iDCs acquire a conventional DC type 1-like transcriptional program, with features of interferon-induced maturation. iDCs secrete inflammatory cytokines and have the ability to engulf, process, and present antigens to T cells. Furthermore, we demonstrate that murine iDCs generated here were able to cross-present antigens to CD8+ T cells. Our reprogramming system should facilitate better understanding of DC specification programs and serve as a platform for the development of patient-specific DCs for immunotherapy.</p>},
  articleno    = {eaau4292},
  author       = {Rosa, Fábio F. and Pires, Cristiana F. and Kurochkin, Ilia and Ferreira, Alexandra G. and Gomes, Andreia M. and Palma, Luís G. and Shaiv, Kritika and Solanas, Laura and Azenha, Cláudia and Papatsenko, Dmitri and Schulz, Oliver and E Sousa, Caetano Reis and Pereira, Carlos Filipe},
  language     = {eng},
  month        = {12},
  number       = {30},
  series       = {Science immunology},
  title        = {Direct reprogramming of fibroblasts into antigen-presenting dendritic cells},
  url          = {http://dx.doi.org/10.1126/sciimmunol.aau4292},
  volume       = {3},
  year         = {2018},
}