On the Discovery of the Dendritic Cell and Its Role in Adaptive Immunity

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1 Jake Noveck Queens College, Biology Senior Ralph M. Steinman, MD (January 14, 1943 September 30, 2011) On the Discovery of the Dendritic Cell and Its Role in Adaptive Immunity Every time that we breathe, eat, drink or get injured, microorganisms are infiltrating our bodies. Some keep us healthy, living within us through mutual benefit. Some are rather more determined to eat our tissues, and some (e.g. viruses) will hijack our cells in order to carry out their own agenda. In addition, as many of our cells continually divide, mutations do accumulate and malignancies will proliferate if left unchecked, and all of these biological threats would very soon kill each and every one of us if it were not for the vigilance and effectiveness of our immune systems. As we age and our resistance becomes less robust, as we become more easily infected, and as emerging cancers transform and become more elusive, it will be achievements in the field of immunology that will allow modern medicine to treat those afflicted effectively, and more safely. One of the biggest recent steps taken toward this goal has to do with the understanding of how the entire system interacts, which, inevitably, involves the crucial links between innate and adaptive immunity. When potentially lethal pathogens such as bacteria penetrate the skin and colonize tissue, the first cells to take action and fight the infection are those involved in the innate immune response, such as macrophages. These cells constantly patrol healthy epithelial tissues and ingest and degrade most types of cellular garbage, and they can also sense and eat up any unwelcome microorganisms. Also residing in these tissues are dendritic cells, whose unique structure was first described by Ralph Steinman in They were named for their whip- like spiny processes (or dendrites) that they use to continuously probe and sample the surrounding microenvironment (1). In many ways, dendritic cells are similar to macrophages, but they are more specialized to provide specific pathogenic information to other immune cells that reside within the lymphatic organs. Once a dendritic cell makes contact with and detects specific patterns on the surface of a pathogen, it ingests, breaks down, and presents pieces of foreign proteins at its own surface within membrane receptors called Major Histocompatibility Complex (MHC) molecules. When an infection becomes severe enough, the local macrophage population gets overwhelmed, and therefore cannot fight the infection alone (13). They call in the cavalry. The missing link: Innate Immunity activates adaptive immunity When an infection gets out of control, the macrophage signals for help from every branch of the immune system. They are these signals that initiate inflammation and induce fever. Other innate immune cells in the blood such as short- lived, macrophage- like neutrophils, home in to the site of infection and help to clear it. At the same time, it is the dendritic cell that gets signaled to stop probing- but to migrate to the nearest lymph node via the lymphoid vessels. It

2 is at this point responsible for (over the course of several days) activating resident T- cells: the major players in the adaptive immune response. (13) Ralph Steinman's team of scientists first identified dendritic cells in the lymphoid tissues of mice and noticed that they accounted for only one percent of all immune cells (1). Before anyone knew anything about the physiological and molecular properties of dendritic cells, it was this early work that demonstrated their overall role in influencing the activities in mixed leukocyte reactions (MLR). To accomplish this, they first isolated the dendritic cells from most other cell types by fractionation. Then, by taking advantage of the dendritic cells' unique morphology, Steinman and colleagues were able to separate them further by their characteristic adherence to glass. When a small portion of the purified dendritic cells from one mouse was transplanted into non- matching lymphoid cell cultures of another mouse, a huge level of lymphocyte activation and divisions occurred. This was indicated by the consumption of significant quantities of radioactive thymidine (a molecule utilized to synthesize new DNA, a process that leads to cell division) by the active cell cultures. This phenomenon could not be reproduced to a similar degree without the initial transplantation of dendritic cells, confirming that they are the potent stimulators for cells of the lymph organs (2,3). If neutrophils are the cavalry, then activated T- cells are the F- 22s equipped with laser guided missiles. Since the discovery of the dendritic cells and their role in orchestrating adaptive immunity, knowledge of the mechanisms involved in providing appropriate immune responses by these cells has expanded dramatically. It is now known, for instance, that the activation of T- cell subtypes depends on which common molecular pattern is picked up by a dendritic cell's various Toll- like receptors (TLR), where the molecular pattern may be bacterial or viral in nature (4). Unlike cell lineages of the innate immune system, each individual T cell (of the billions present at any given time within a lymphatic organ) has a unique surface receptor encoded by genes that are formed by random assembly of small gene segments. The T- cell receptor can associate with one unique MHC- bound antigen that is not expressed by the body itself (9). In other words, if an antigen- presenting dendritic cell migrates to a lymph node, chances are there will be one or more naive (undifferentiated) T- cells that have receptors able to recognize the foreign antigens (whether they be bacterial, viral, or cancer cells expressing such antigens). Once this recognition occurs, the associated naive T- cells are signaled by the dendritic cell to proliferate (This type of activity is similar to that which occurs during MLR, as previously mentioned) as well as to differentiate into activated regulatory (Treg), helper (Th), or killer (cytotoxic, CTL) T- cells. Each of these subtypes plays a specific part in combating different types of disease. In short, killer T- cells possess the ability to recognize and directly kill a cancerous or virus- infected cell that presents the same MHC: antigen combination as the dendritic cell that innervated it. T helper cells can stimulate innate immune cells to more vigorously detect and wipe out a specific pathogen. Tregs have the unique ability to suppress the activity of other immune cells so that collateral damage to healthy tissue can be avoided as much as possible (13).

3 The more that is known about how all immune cells interact with each other and within their surrounding microenvironment, the more possibilities open up for the treatment of many illnesses related to infection, cancer, autoimmune diseases and organ transplant rejection. For example, to start off the proliferative phase of T- cell mediated immunity, a dendritic cell presents its antigen- loaded MHC molecules to the complementary T- cell receptors, and it also interacts through additional B7 costimulatory molecules with CD28 costimulatory molecules located on the surface of the T- cell. This region of activity between the two cell surfaces is called the immunological synapse. High levels of interaction between costimulatory molecules generates a powerful signal cascade throughout both cells, and it is at this point where the T- cell begins to divide and differentiate. At the same time, the T- cell can regulate this process by producing CTLA- 4 inhibitory molecules that interact much more avidly and compete to bind with B7 molecules. This interaction attenuates an otherwise out- of- control signal that could lead to a severe inflammatory or autoimmune reaction. By using a method called checkpoint blockade, It is now possible to interfere with the communication between these molecules. For instance, in cases where a heightened immune response is necessary to destroy an evasive tumor, it is plausible to specifically block the binding action of CTLA- 4 in order to evoke a higher level of T- cell proliferation. On the flip side, by introducing a CTLA- 4- like fusion protein that further deactivates B7 molecules at the immunological synapse, the production of an over- reactive T- cell population (caused by autoimmune disease or organ transplant rejection) can also be avoided (5,6). The checkpoint blockade is one of many levels of strategy where T- cell mediated immunity can be controlled. Much like infectious agents, many cancers have the tendency to evade and not be destroyed by killer T- cells. There are many ways they can do this, and one way is by using the body's own immune system against itself to activate immunosuppressive Tregs. (7) One clinical strategy is to assist dendritic cells to acknowledge the presence of some evasive tumors by exposing the dendritic cells to tumor antigens, while at the same time provoking the dendritic cells' TLRs with synthetic viral RNA (this mimics presence of virus, and induces subsequent proliferation of CTLs). With this strategy, treatment of cancer seems plausible for the future, and such strategies may even prove to be more effective than most current cancer treatments (8). It was a similar type of experimental therapy, in fact, that Steinman confidently decided to undergo when he was diagnosed with pancreatic cancer four years ago. The probability of survival after one year for individuals diagnosed with this disease is currently less than five percent (9). He argued that the emphasis in pursuing conventional cancer treatments over immunological treatments is illogical, because conventional treatments only target one pathway to kill a tumor. This makes it relatively easy for a fraction of the cancer cell population to escape, where they will continue to divide and will more easily resist therapies that have been effective previously. Therefore, by coming up with a combinational plan of attack that involves the checkpoint blockade, selective presentation of tumor antigens, and manipulation of TLRs, immunological medicine has the potential to procure a "unique targeted therapy because it is specific, multifaceted, durable, and typically nontoxic." (5) Generally, we think of vaccinations as injections that guard us against infections caused by specific strains of viruses or bacteria, but it has become more apparent that the arms of the

4 immune system reach far beyond this purpose. With the ongoing efforts to solve the problems of the most common diseases afflicting people today, vaccinations could take on a whole new color. It is comforting to know that future medical strides, such as optimization of the antigen presenting capacity of the dendritic cell so that an effective HIV vaccine can be produced (11), or the holding off of life- threatening cancers, are within our reach today. The best part is that any person with a healthy immune system has the T- cells to accomplish this! Unfortunately, the rate of advancement in developing these therapies for use with patients has been disappointing. Such slow progress can be attributed to a lack of government interest and academic collaboration (5), but it certainly cannot be attributed to a lack of ideas. Stages of dendritic cell maturation upon induced migration by inflammatory signaling.

5 REFERENCES: 1) Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantization, tissue distribution. J Exp Med. 1973, 137: ) Steinman, R., & Cohn, Z. (1974). Identification of a novel cell type in peripheral lymphoid organs of mice. II. J Exp Med, 139, ) Steinman, R. M., & Witmer, M. D. (1978). Lymphoid dendritic cells are potent stimulators of the primary mixed leukocyte reaction in mice. Proc. Nati. Acad. Sci, 75(10), ) Medzhitov R, Preston- Hurlburt P, Janeway CA. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997, 388: ) Steinman, R. (2009). Some Scientific and Organizational Challenges in Cancer Immunology. Cancer Vaccines: Ann. N.Y. Acad. Sci, 1174, ) Sakaguchi, S., & Win, K. (2011). Damping by Depletion. Science, 332, ) Vesely, M. D., Kershaw, M. H., Schreiber, R. D., & Smyth, M. J. (2011). Natural Innate and Adaptive Immunity to Cancer. Annu. Rev. Immunol, 29, ) Gilboa, E., Nai, S. K., & Lyerly, H. K. (1998). Immunotherapy of cancer with dendriticcell-based vaccines. Cancer Immunol Immunother, 46, ) Steinman, R. M., & Banchereau, J. (2007). Taking dendritic cells into medicine. Nature, 449, ) Steenhuysen, J., Nichols, M., & Reuters. (n.d.). Nobel Prize winner Ralph Steinman's last big experiment: Himself. Montreal Gazette - Breaking News, Quebec, Opinion, Multimedia & More. Retrieved December 9, 2011, from eriment+himself/ /story.html 11) Piguet, V., & Ralph, S. (2007). The interaction of HIV with dendritic cells: outcomes and pathways. Trends in Immunology, 28(11), ) Steinman, R. (2008). Dendritic Cells In Vivo: A Key Target for a New Vaccine Science. Immunity, 29, ) Murphy, K. P., Travers, P., Walport, M., & Janeway, C. (2012). Janeway's Immunobiology (8th ed.). New York: Garland Science.