Direct Reprogramming of Mouse and Human Fibroblasts into Conventional Dendritic Cells Type 1
(2022) In Molecular Immunology 150. p.22-22- Abstract
- Cell fate reprogramming of adult cells towards pluripotency or unrelated somatic cell-types has been explored in the context of regenerative medicine. Dendritic cells (DCs) are professional antigen presenting cells (APCs) specialized in the recognition, processing and presentation of antigens to T-cells, inducing adaptive immunity. In particular, the mouse conventional DCs type 1 (cDC1) subset or DC1 human equivalent excel on the ability to perform antigen cross-presentation, a critical step for inducing cytotoxic responses. We hypothesized that the unique properties of cDC1s could be induced in unrelated cell-types, allowing the direct control of immune responses with cell reprogramming.
Here, the requirements to induce cDC1s... (More) - Cell fate reprogramming of adult cells towards pluripotency or unrelated somatic cell-types has been explored in the context of regenerative medicine. Dendritic cells (DCs) are professional antigen presenting cells (APCs) specialized in the recognition, processing and presentation of antigens to T-cells, inducing adaptive immunity. In particular, the mouse conventional DCs type 1 (cDC1) subset or DC1 human equivalent excel on the ability to perform antigen cross-presentation, a critical step for inducing cytotoxic responses. We hypothesized that the unique properties of cDC1s could be induced in unrelated cell-types, allowing the direct control of immune responses with cell reprogramming.
Here, the requirements to induce cDC1s were investigated using combinatorial overexpression of Transcription Factors (TFs) in Clec9a-tdTomato mouse fibroblasts. In the hematopoietic system, Clec9a specifically marks the DC lineage, including all conventional dendritic cells type 1 (cDC1). We have identified PU.1, IRF8 and BATF3 (PIB) as sufficient and necessary to induce Clec9a reporter activation, establish DC morphology and activate a cDC1 transcriptional program in mouse fibroblasts. The over- expression of PIB ignites the expression of DC markers including CD103, XCR1, MHC-I, MHC-II and co-stimulatory molecules. Functionally, Induced DCs (iDCs) secrete inflammatory cytokines and engulf, process, present and cross-present antigens to CD4+ and CD8+ T cells, respectively. Additionally, we have demonstrated that combined expression of PIB factors induces DC1 reprogramming in human fibroblasts. Human iDC1s acquire DC morphology, express DC1 markers, including Clec9a, CD141 and the co-stimulatory molecules CD40, CD80 and CD86, and acquire a DC1 transcriptional signature at the single cell level. Interestingly, DC1 reprogramming efficiency can be enhanced 70-fold by supplementing culture media with inflammatory cytokines, suggesting a regulatory role of inflammation during DC1 reprogramming.
Hence, we provide evidence that antigen presentation and cross-presentation can be dynamically programmed by a small combination of TFs. These findings provide insights into cDC1 specification and a platform for developing cancer immunotherapies based on cell reprogramming. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/db11ebbf-47cd-4820-8024-6f7f1f4b7c57
- author
- Fiúza Rosa, Fábio LU ; Pires, Cristiana LU ; Kurochkin, Ilia LU ; Ferreira, Alexandra G. LU ; Schulz, Oliver ; Reis e Sousa, Caetano and Pereira, Carlos-Filipe LU
- organization
- publishing date
- 2022-10-01
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Molecular Immunology
- volume
- 150
- pages
- 22 - 22
- publisher
- Pergamon Press Ltd.
- ISSN
- 1872-9142
- DOI
- 10.1016/j.molimm.2022.05.076
- language
- English
- LU publication?
- yes
- id
- db11ebbf-47cd-4820-8024-6f7f1f4b7c57
- date added to LUP
- 2023-08-10 21:15:57
- date last changed
- 2023-08-11 11:06:08
@misc{db11ebbf-47cd-4820-8024-6f7f1f4b7c57, abstract = {{Cell fate reprogramming of adult cells towards pluripotency or unrelated somatic cell-types has been explored in the context of regenerative medicine. Dendritic cells (DCs) are professional antigen presenting cells (APCs) specialized in the recognition, processing and presentation of antigens to T-cells, inducing adaptive immunity. In particular, the mouse conventional DCs type 1 (cDC1) subset or DC1 human equivalent excel on the ability to perform antigen cross-presentation, a critical step for inducing cytotoxic responses. We hypothesized that the unique properties of cDC1s could be induced in unrelated cell-types, allowing the direct control of immune responses with cell reprogramming.<br/><br/>Here, the requirements to induce cDC1s were investigated using combinatorial overexpression of Transcription Factors (TFs) in Clec9a-tdTomato mouse fibroblasts. In the hematopoietic system, Clec9a specifically marks the DC lineage, including all conventional dendritic cells type 1 (cDC1). We have identified PU.1, IRF8 and BATF3 (PIB) as sufficient and necessary to induce Clec9a reporter activation, establish DC morphology and activate a cDC1 transcriptional program in mouse fibroblasts. The over- expression of PIB ignites the expression of DC markers including CD103, XCR1, MHC-I, MHC-II and co-stimulatory molecules. Functionally, Induced DCs (iDCs) secrete inflammatory cytokines and engulf, process, present and cross-present antigens to CD4+ and CD8+ T cells, respectively. Additionally, we have demonstrated that combined expression of PIB factors induces DC1 reprogramming in human fibroblasts. Human iDC1s acquire DC morphology, express DC1 markers, including Clec9a, CD141 and the co-stimulatory molecules CD40, CD80 and CD86, and acquire a DC1 transcriptional signature at the single cell level. Interestingly, DC1 reprogramming efficiency can be enhanced 70-fold by supplementing culture media with inflammatory cytokines, suggesting a regulatory role of inflammation during DC1 reprogramming.<br/><br/>Hence, we provide evidence that antigen presentation and cross-presentation can be dynamically programmed by a small combination of TFs. These findings provide insights into cDC1 specification and a platform for developing cancer immunotherapies based on cell reprogramming.}}, author = {{Fiúza Rosa, Fábio and Pires, Cristiana and Kurochkin, Ilia and Ferreira, Alexandra G. and Schulz, Oliver and Reis e Sousa, Caetano and Pereira, Carlos-Filipe}}, issn = {{1872-9142}}, language = {{eng}}, month = {{10}}, note = {{Conference Abstract}}, pages = {{22--22}}, publisher = {{Pergamon Press Ltd.}}, series = {{Molecular Immunology}}, title = {{Direct Reprogramming of Mouse and Human Fibroblasts into Conventional Dendritic Cells Type 1}}, url = {{http://dx.doi.org/10.1016/j.molimm.2022.05.076}}, doi = {{10.1016/j.molimm.2022.05.076}}, volume = {{150}}, year = {{2022}}, }