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Inducing plasmacytoid dendritic like-cells with cell reprogramming

Pastor Gómez, Jennyfer Lizeth (2020) MOBN03 20192
Degree Projects in Molecular Biology
Popular Abstract
Inducing plasmacytoid dendritic-like cells with cell reprogramming

Dendritic cells (DCs) are a type of immune cell with the ability to take up self and foreign molecules, process them and present a small part of them to T cells, another immune cell that can generate specific immune responses. DCs are subdivided in conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs). cDCs are further subdivided into cDCs type I and cDCs type II, each specialized in activate a specific type of T cell. Similarly to cDCs, pDCs express on their surface major histocompatibility complexes type I (MHCI) and type II (MHCII), which allows them to induce T-cell responses; however, their main function is to secrete large amounts of type I... (More)
Inducing plasmacytoid dendritic-like cells with cell reprogramming

Dendritic cells (DCs) are a type of immune cell with the ability to take up self and foreign molecules, process them and present a small part of them to T cells, another immune cell that can generate specific immune responses. DCs are subdivided in conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs). cDCs are further subdivided into cDCs type I and cDCs type II, each specialized in activate a specific type of T cell. Similarly to cDCs, pDCs express on their surface major histocompatibility complexes type I (MHCI) and type II (MHCII), which allows them to induce T-cell responses; however, their main function is to secrete large amounts of type I interferons (IFNs), which are critical molecules in the immune response to viruses.

Due to their extraordinary ability to induce anti-viral immune responses, in recent years, pDCs have become an attractive target for the development of immunotherapies. However, current immunotherapies based on dendritic cells, are usually limited by the low number of these cells circulating in the blood. A good way to address this issue is through cell reprogramming, an emergent way of understanding and controlling adult cell fate. In cell reprogramming, a cell can be forced to change to a different state or type by introducing exogenous DNA coding for transcription factors (TFs). These proteins have the ability to bind to the DNA and modify the expression of specific genes, which will ultimately cause the cell to change.

In 2018 members of our group successfully reprogrammed mouse and human skin cells into DCs type I using a pool of TFs containing PU.1, IRF8, and BATF3. In this project, we hypothesized that by modifying the combination of TFs previously found by our group, it was possible to reprogram cells s into pDC-like cells instead of cDCs type I. For this, we identified a list of 38 candidate TFs that are specifically expressed in pDCs and had a previously known role in pDC development or function. Then, we introduced the TFs into embryonic skin cells isolated from Clec9a-reporter mice using lentiviral particles in combinations of two and later on, three TFs. In this system, any MEF that starts expressing the DC-specific gene Clec9a will be identifiable for the simultaneous expression of the reporter fluorescent protein tdTomato.

We have identified a combination of two TFs that was sufficient to induce reporter activation and expression of surface molecules usually found on DCs. The individual addition of some transcription factors to this initial combination increases the efficiency of the reprogramming process. Moreover, preliminary results assessing cytokine secretion for some combinations have shown that reporter expressing cells can secrete type I IFN, thus, suggesting similar functional properties to natural pDCs. Future experiments will be necessary to further characterize these cells in terms of surface molecules and gene profiles to investigate their similarity with natural-occurring pDCs. Future advances in this study could potentially offer the opportunity to use patient-specific skin-cells as an alternative source to produce pDCs, which is of particular interest for the development of immunotherapies against viral diseases and neoplasias.

Master’s degree project in Molecular Biology (60 credits) 2020
Department of Biology, Lund University

Supervisor: Filipe Pereira
Co-supervisor: Cristiana Pires
Molecular Medicine and Gene Therapy, Faculty of Medicine, Lund University (Less)
Please use this url to cite or link to this publication:
author
Pastor Gómez, Jennyfer Lizeth
supervisor
organization
course
MOBN03 20192
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
9030369
date added to LUP
2020-10-02 13:19:44
date last changed
2020-10-02 13:19:44
@misc{9030369,
  author       = {{Pastor Gómez, Jennyfer Lizeth}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{Inducing plasmacytoid dendritic like-cells with cell reprogramming}},
  year         = {{2020}},
}