Dendritic Cells
Stars that guide the defense response
Credit: Art by Nelly Aghekyan. Set in motion by Dr Emanuele Petretto. Words by Dr Nowrin Ahmed. Coordinator: Dr Masia Maksymowicz, Series Director: Dr Radhika Patnala
#Extraordinarycelltypes #sciart #lifescience
Where it all began
It will surprise you to find that a very small, but mighty group of cells known as dendritic cells (DC) trigger the most powerful immune response. Since their discovery over 50 years ago, they have emerged as essential players in immunology. Named for their branch-like protrusions, commonly found in neurons, from the Greek word déndron meaning “tree,” dendritic cells were first characterized by Steinman and Cohn in 1973 as a rare type of murine spleen cells that were phagocytic with dendrite-like appendages (1). In fact, they were first described by Paul Langerhans as neurons because of their dendritic branches. Yet, their significance in immunology was recognized by Steinman for which he was awarded the Nobel Prize in Physiology in Medicine in 2011 (2, 3). Steinman and his team showed that dendritic cells initiated stronger ‘mixed lymphocyte reactions’ than B and T lymphocytes and macrophages, which took the immunology field by storm (4). Their continued work established dendritic cells as the most significant ‘professional’ antigen presenting cells (APCs) that guide innate and adaptive immunity. Further research showed that these cells are key players in infection, chronic inflammatory reactions, and cancer (3).
Dendritic cells exhibit various characteristics
Dendritic cells have highly diverse ontogeny and functions, existing as conventional DCs, plasmacytoid DCs, and inflammatory DCs (5). Conventional DCs and plasmacytoid DCs are present in the blood, while inflammatory DCs are found in tissues (6).
These cells derive from bone marrow progenitors, lymphoid organs, and monocytes in peripheral blood vessels. Conventional dendritic cells can be further divided into type 1 (cDC1) and type 2 (cDC2) (7). Additionally, inflammatory DCs differentiate from monocytes in peripheral blood vessels in response to inflammatory conditions (8). These cells have been the subject of intense debate since their discovery with many unresolved questions regarding their developmental and functional properties.
Dendritic cells are powerful orchestrators of the immune system
Dendritic cells gained their recognition as potent ‘professional’ antigen-presenting cells that link innate immune response with adaptive immune response. They sense pathogens in the external environment, engulf and process them so that T lymphocytes can recognize them, thus activating the immune response. Additionally, they ensure that the immune system does not attack harmless cells in the body (9).
They can integrate signals from the environment through membrane-bound pattern recognition receptors (PPRs), such as toll-like receptors, with which they detect a variety of pathogen-associated molecular patterns (PAMPS) and damage-associated molecular patterns (DAMPs) (6). Their presence in almost all tissues in the body, including peripheral tissues such as the skin and lung, enables them to detect foreign substances, such as invading microorganisms as well as damaged or cancerous cells, and present them to naïve T cells by migrating into peripheral blood vessels or draining lymph nodes (10, 11).
Diverse cells trigger diverse immune responses
The type of immune response initiated by T cells depends on the dendritic cell subtype involved. One unique function performed by dendritic cells is cross-priming, a process through which uninfected dendritic cells activate cytotoxic T lymphocytes by a mechanism known as cross-presentation. Cross-presentation involves the loading of exogenous antigens from invading pathogens or damaged cells onto major histocompatibility complex (MHC) molecules in dendritic cells. These are then presented to T lymphocytes. This presentation of exogenous antigens to T lymphocytes can lead to both cross-priming or cross-tolerance which has major implications in defense against pathogens or tumors (12–14).
There is great diversity in how cross-presentation occurs. Different types of dendritic cells target specific microorganisms through distinct pathways, triggering the release of cytokines and co-stimulatory molecules to initiate an immune response. For example, cDC1 presents antigens from intracellular viruses and bacteria to CD8+ T cells whereas cDC2 presents antigens from extracellular bacteria, viruses and fungi to CD4+ T helper cells (7,15).
Dendritic cells fight cancer
Additionally, extensive research in the treatment of cancer, which is a major cause of death worldwide, has focused on the function of dendritic cells in response to cancer. Numerous labs have shown that dendritic cells play a key role in antitumor responses. cDC1 exhibits potent antitumor activity by migrating to the tumor site, responding to antigens from tumor cells, and cross-presenting these antigens to CD8+ T cells to initiate a robust immune response. Other subtypes of dendritic cells also migrate to the tumor site where they activate tumor-specific T helper type 1 cells, as well as recruit Natural Killer cells by releasing interleukin-12 (7, 17). On the other hand, pDCs behave differently in a cancer microenvironment (the surrounding area near the tumor) where they activate T regulatory cells and are unable to produce interferon, resulting in immunosuppression of the tumor response (16).
Can DCs be utilized in cancer immunotherapy?
Dendritic cells play a role in cancer treatment, since they are recruited by chemotherapy-induced cell death. For example, chemotherapy drugs such as doxorubicin or oxaliplatin initiate immunogenic cell death (ICD) where death or damage of tumor cells leads to the secretion of signals known as ‘alarmins’. ATP is an example of an ‘alarmin’ which activates the cross-presentation of tumor-associated antigens to CD8+ T cells by dendritic cells, facilitating the killing of tumor cells (18, 19).
Interestingly, the involvement of dendritic cells in cancer treatment can be further exploited to develop novel therapeutic approaches in immunotherapy. Many scientists are testing how the administration of various substances (e.g. adjuvants, growth factors, recombinant tumor-associated antigen-expressing viruses, or tumor cell lysate antigens) can affect the recruitment of dendritic cells. Additionally, various clinical studies performed to test dendritic cell vaccines for cancer have yielded promising results (19). Therefore, unlocking the secrets of dendritic cell development and function can help us devise ways to utilize these cells in the fight against pathogens.
Recognizing and appreciating the labs working in this space
- Tumor Immunology Lab, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands. https://tumor-immunology-lab.nl/vision/ , Twitter: @TIL_Radboudumc
- Martin Guilliams Lab, Ghent University, Ghent, Belgium. https://guilliamslab.sites.vib.be/en#/ , Twitter: @MartinGuilliams
- Department of Immunology, Kanazawa Medical University, Ishikawa, Japan. https://www.kanazawa-med.ac.jp/~serol/Immunology/Top_Page.html
- Epigenetics and Immune Disease Group, Josep Carreras Research Institute, Barcelona, Spain. https://www.carrerasresearch.org/en/research/epigenetics-and-immune-disease
- Ronchese Laboratory, Malaghan Institute of Medical Research, Wellington, New Zealand. https://www.malaghan.org.nz/our-expertise/research-groups/ronchese-laboratory/
- Haniffa Lab, Newcastle University, Newcastle upon Tyne, UK. https://haniffalab.com/ , Twitter: @Muzz_Haniffa
- Manfred Lutz lab, University of Würzburg, Würzburg, Germany. https://www.virologie.uni-wuerzburg.de/en/immunobiology/immunobiological-lab-groups/research-group-prof-dr-manfred-lutz/
- Christian Kurts Laboratory, University Clinic of the Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany. https://www.immei.de/research/christian-kurts-laboratory , Twitter: @chrkurts
- Ploegh lab, Boston Children’s Hospital, Boston, Massachusetts 02142, USA. https://www.childrenshospital.org/research/labs/ploegh-lab-research , Twitter: @PloeghLab
- Immune Responses to Cancer Lab, Université Paris Descartes, Paris, France. https://institut-curie.org/team/amigorena?_gl=1*1of39sd*_up*MQ..*_ga*MTAzMTM1MjUyMy4xNzEzNDYxNTA2*_ga_K3EEXPN8JN*MTcxMzQ2MTUwNS4xLjEuMTcxMzQ2MTUzMC4wLjAuMA..*_ga_179E58JVNW*MTcxMzQ2MTUwNS4xLjEuMTcxMzQ2MTUzMC4wLjAuMA.. , Twitter: @institut_curie
References
1. Steinman, R. M., and Z. A. Cohn. “Identification of a Novel Cell Type in Peripheral Lymphoid Organs of Mice. I. Morphology, Quantitation, Tissue Distribution.” J Exp Med 137 5 (1973): 1142–62.
2. Rowley, D. A., and F. W. Fitch. “The Road to the Discovery of Dendritic Cells, a Tribute to Ralph Steinman.” Cell Immunol 273 2 (2012): 95–8.
3. Van Spriel, A. B., and E. C. de Jong. “Dendritic Cell Science: More Than 40 Years of History.” J Leukoc Biol 93 1 (2013): 33–8.
4. Steinman, R. M., and M. D. Witmer. “Lymphoid Dendritic Cells Are Potent Stimulators of the Primary Mixed Leukocyte Reaction in Mice.” Proc Natl Acad Sci U S A 75 10 (1978): 5132–6.
5. Guilliams, M., et al. “Dendritic Cells, Monocytes and Macrophages: A Unified Nomenclature Based on Ontogeny.” Nat Rev Immunol 14 8 (2014): 571–8.
6. Morante-Palacios, O., et al. “Tolerogenic Dendritic Cells in Autoimmunity and Inflammatory Diseases.” Trends Immunol 42 1 (2021): 59–75.
7. Kvedaraite, E., and F. Ginhoux. “Human Dendritic Cells in Cancer.” Sci Immunol 7 70 (2022): eabm9409.
8. Coillard, A., and E. Segura. “In Vivo Differentiation of Human Monocytes.” Front Immunol 10 (2019): 1907.
9. Kotsias, F., I. Cebrian, and A. Alloatti. “Antigen Processing and Presentation.” Int Rev Cell Mol Biol 348 (2019): 69–121.
10. Haniffa, M., et al. “Human Tissues Contain Cd141hi Cross-Presenting Dendritic Cells with Functional Homology to Mouse Cd103+ Nonlymphoid Dendritic Cells.” Immunity 37 1 (2012): 60–73.
11. Lutz, M. B., and G. Schuler. “Immature, Semi-Mature and Fully Mature Dendritic Cells: Which Signals Induce Tolerance or Immunity?” Trends Immunol 23 9 (2002): 445–9.
12. Kurts, C., B. W. Robinson, and P. A. Knolle. “Cross-Priming in Health and Disease.” Nat Rev Immunol 10 6 (2010): 403–14.
13. Joffre, O. P., et al. “Cross-Presentation by Dendritic Cells.” Nat Rev Immunol 12 8 (2012): 557–69.
14. Vyas, J. M., A. G. Van der Veen, and H. L. Ploegh. “The Known Unknowns of Antigen Processing and Presentation.” Nat Rev Immunol 8 8 (2008): 607–18.
15. Hilligan, K. L., and F. Ronchese. “Antigen Presentation by Dendritic Cells and Their Instruction of Cd4+ T Helper Cell Responses.” Cell Mol Immunol 17 6 (2020): 587–99.
16. Reizis, B. “Plasmacytoid Dendritic Cells: Development, Regulation, and Function.” Immunity 50 1 (2019): 37–50.
17. Marciscano, A. E., and N. Anandasabapathy. “The Role of Dendritic Cells in Cancer and Anti-Tumor Immunity.” Semin Immunol 52 (2021): 101481.
18. Galluzzi, L., et al. “Immunogenic Cell Death in Cancer and Infectious Disease.” Nat Rev Immunol 17 2 (2017): 97–111.
19. Wculek, S. K., et al. “Dendritic Cells in Cancer Immunology and Immunotherapy.” Nat Rev Immunol 20 1 (2020): 7–24.
About the author:
Dr. Nowrin Ahmed
Content Editor The League of Extraordinary Cell Types, Sci-Illustrate Stories
Dr. Nowrin Ahmed has a PhD in Behavioral and Neural Sciences from Rutgers University-Newark (NJ, USA) where she studied the interactions between the midline thalamus and the amygdala. Currently, she is a post-doctoral fellow at Rutgers University — Newark where she is studying amygdala circuits. Dr. Nowrin enjoys sharing the beauty of science with diverse audiences.
About the artist:
NELLY AGHEKYAN
Contributing Artist The League of Extraordinary Cell Types, Sci-Illustrate Stories
Nelli Aghekyan, did a bachelor’s and master’s in Architecture in Armenia, after studying architecture and interior design for 6 years, she concentrated on her drawing skills and continued her path in the illustration world. She works mainly on children’s book illustrations, some of her books are now being published. Currently living in Italy, she works as a full-time freelance artist, collaborating with different companies and clients.
About the animator:
DR. EMANUELE PETRETTO
Animator The League of Extraordinary Cell Types, Sci-Illustrate Stories
Dr. Petretto received his Ph.D. in Biochemistry at the University of Fribourg, Switzerland, focusing on the behavior of matter at nanoscopic scales and the stability of colloidal systems. Using molecular dynamics simulations, he explored the delicate interaction among particles, interfaces, and solvents.
Currently, he is fully pursuing another delicate interaction: the intricate interplay between art and science. Through data visualization, motion design, and games, he wants to show the wonders of the complexity surrounding us.
About the series:
The League of Extraordinary Cell types
The team at Sci-Illustrate and Endosymbiont bring to you an exciting series where we dive deep into the wondrous cell types in our body, that make our hearts tick ❤.
