In 1973, a young scientist by the name of Ralph Steinman became the first person to identify and describe an unusual immune cell called the dendritic cell. At a time when immunology was dominated by research on cell types known as B cells and T cells, most scientists initially considered these comparatively rare, strikingly branched cells discovered by Steinman to be nothing more than a curious oddity. Steinman and his colleagues fought an uphill battle advocating the importance of these cells in controlling the immune response, and it took almost a decade for their ideas to gain significant traction in the scientific community. Despite this initial struggle, Steinman’s ideas eventually revolutionized immunology and the greater medical field to such a degree that this year he was awarded the Noble Prize in Medicine – albeit, tragically, three days after he passed away from pancreatic cancer [].

What are dendritic cells?

Dendritic cells act as critical sentinels that can trigger as well as dictate the type of an immune response. The crux of this notion is that not all immune responses are made equal; for instance, your body reacts differently to viruses and bacteria, and this is for good reasons. If the body were to mount the same immune response to both kinds of pathogens, the resulting inefficiency and lack of precision would likely translate into a far less effective defense.

Strategically located in areas that are vulnerable to infection, such as the respiratory tract, intestine and skin, dendritic cells actively survey their local environment for signs of pathogens (disease-causing organisms) and damage to the body’s own cells. They use their highly mobile and elongated arms (Figure 1) to scan various tissues of the body, catching and consuming various particles near them, known as antigens, which are produced by pathogens.  After consuming these antigen particles, the dendritic cells break them down into smaller components, which are then displayed on the cells’ surface to broadcast the contents of their recent meals.

Figure 1. A dendritic cell under the microscope. Source: PLoS Pathogens

Nearby T cells, upon interacting with these “antigen-displaying” dendritic cells, will become activated if the dendritic cell itself was activated previously during an encounter with a pathogen (see below). Activated T cells can then carry out a number of immune functions. For example, they can amplify the magnitude of the immune response by producing molecules called cytokines to activate other cells. Activated T cells can also directly kill infected host cells to prevent spreading of the infection, or “remember” what an infection looks like so that they can more rapidly respond upon future re-infection by the same pathogen.

If T cells cannot properly understand the messages from dendritic cells, or if dendritic cells cannot generate the proper messages for the T cells, then the immune response suffers dramatically. This is the case during, for example, the frequent and oftentimes severe bacterial infections in patients lacking the gene called MyD88 []. This gene is turned on once a dendritic cell interacts with a pathogen, and is necessary for the dendritic cell to make a variety of molecules that activate T cells.

The crosstalk between dendritic cells and T cells is called antigen presentation. Different T cells respond to different signals presented on the dendritic cell surface. If a dendritic cell presents an antigen to the appropriate T cell, then the dendritic cell can direct the T cell to behave in a certain way by generating cytokines and trigger what is called an inflammatory response.

The problem is that pathogens aren’t the only things that dendritic cells can scoop up from the environment. Dendritic cells can take up anything near them – including byproducts of our own bodies. Therefore, to prevent autoimmune reactions (where T cells attack our bodies’ own healthy cells), dendritic cells only produce cytokines responsible for activating T cells if they also detect key markers of bacteria or viruses, such as components of the bacterial cell wall or viral genetic material, that are collectively known as pathogen associated molecular patterns (PAMPs). If a dendritic cell finds a PAMP, it becomes activated and makes specific cytokines to wake up the rest of the immune system. Combinations of different types of cytokines generate the various specialized types of immune responses.

Without the help of dendritic cells, T cells cannot react correctly to fend off an infection. This, in turn, affects the cells that receive instructions from T cells. Inappropriate dendritic cell function can thus have a domino effect on many downstream events of an immune response (Figure 2). Therefore, the consequences of defective dendritic cells resonate far beyond just impaired T cell response. By integrating and translating various environmental signals into a robust immunological message, dendritic cells are indispensible for triggering the correct type of response to rid the body of numerous types of pathogens such as fungi, bacteria, parasites or viruses.

Figure 2. Dominoes set up for a chain reaction. Source: Wikimedia Commons user aussiegall

Taking dendritic cells to the clinic

Therapies targeting dendritic cell behavior possess therapeutic potential in many different contexts, including cancer, infection, allergies, asthma, autoimmunity, transplantation, and vaccine development. Blocking the activity of pro-inflammatory cytokines produced by dendritic cells is a key strategy in the fight against a number of autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease. Cytokines such as IL-6 and IL-12, both critical in shaping the type and magnitude of T cell responses, are directly targeted by the antibody therapies Tocilizumab (for rheumatoid arthritis) and Stelara (for psoriasis), respectively [3, 4]. Furthermore, insights into dendritic cell maturation signals such as PAMPs have improved vaccine technology. For example, the compound monophosphoryl lipid A (MPL) was specifically developed to target dendritic cells and force them to robustly activate the immune response by mimicking a component of the bacterial cell wall []. This compound is part of the recently developed cervical cancer vaccine Cervarix, which has shown near complete efficacy in preventing certain viral infections responsible for 70% of cervical cancers [].

But perhaps the most dramatic example of engineering the behavior of dendritic cells involves Ralph Steinman himself. When diagnosed with stage IV pancreatic cancer and faced with a 5% chance of surviving more than 1 year, Steinman used dendritic cell-based experimental therapies based largely on his own research (similar to Provenge therapy). He isolated his own dendritic cells, “educated” them by feeding them pieces of his own tumor, primed them to become inflammatory through the use of vaccines components like MPL, and then re-injected them into his body in the hope of galvanizing his immune system to fight off the cancer. Unfortunately he ultimately succumbed to the disease, but that was only after fighting back for more than four years.

Of course, nobody can pinpoint exactly how Steinman beat the odds for so long, but his own dendritic cell therapy may have played a role. And while the Nobel Prize ceremony next month will fall inescapably under the shadow of his untimely passing, his long unwavering faith in the promise of dendritic cells, clinical successes to date, and exciting new treatments under development all solidify our acceptance of the dendritic cell as a key regulator of the immune response.

Sarah Bettigole is a graduate student in immunology at Harvard Medical School.

References:

1. Julie Steenhuysen and Michelle Nichols, 2011. “Nobel Prize winner Ralph Steinman’s last big experiment: Himself”, Reuters. http://www.montrealgazette.com/life/Nobel+Prize+winner+Ralph+Steinman+last+experiment+Himself/5520075/story.html

2. Bernuth H et al., 2008. Pyogenic bacterial infections in hHumans with MyD88 deficiency, Science.  http://www.ncbi.nlm.nih.gov.ezp-prod1.hul.harvard.edu/pmc/articles/PMC2688396/?tool=pubmed

3. Carol Eustice, 2010. “Actemra (tocilizumab) – What You Should Know:  Actemra Appears Effective for Adult and Juvenile Rheumatoid Arthritis”, About.com. http://arthritis.about.com/od/brms/a/actemra.htm

4. Joanna Broder, 2010. “Stelara Beats Enbrel in Psioriasis,” WebMD. ; Elizabeth Boskey, 2011.  “Before You Get the HPV Vaccine: Is Gardasil or Cervarix the HPV Vaccine for Me?”,  About.com. http://std.about.com/od/hpv/bb/HPV-Vaccine-Comparison-Gardasil-Cervarix.htm

5.  Derek T O’Hagan, 2007. “New Generation Vaccine Adjuvants”, Novartis Vaccines and Diagnostics.  http://www.roitt.com/elspdf/Newgen_Vaccines.pdf

6.  2009. “Human Papillomavirus (HPV) Vaccines”, National Cancer Institute. http://www.cancer.gov/cancertopics/factsheet/prevention/HPV-vaccine

Link of Interest:

Flash animation about dendritic cells from the lab webpage of Ralph Steinman: http://lab.rockefeller.edu/steinman/dendritic_intro/interactiveFlash

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