A cell of a discovery
Research following the discovery of dendritic cells 35 years ago is profoundly changing the science of immunology and its many interfaces with medicine.
DENDRITIC cells were discovered in 1973 by Ralph Steinman and Zanvil A. Cohn at the Rockefeller University. At the time, Steinman and Cohn were studying spleen cells to understand the induction of immune responses in a major lymphoid organ of the mouse.
They were aware from research in other laboratories that the development of immunity by mouse spleen required both lymphocytes and “accessory cells”, which were of uncertain identity and function. The accessory cells were thought to be typical macrophages (a type of white blood cell that engulfs and digests cellular debris and pathogens), but despite extensive laboratory experience with macrophages, Steinman and Cohn encountered a population of cells with unusual shapes and movements that had not been seen before. Because the cells had unusual tree-like or “dendritic” processes, Steinman named them “dendritic cells”
.
When Steinman evaluated this population of cells, they had little, if any, resemblance to the well-known macrophages. Accordingly, these cells were identified as novel cells having distinct properties, and eventually, functions.
Functional studies revealed their potent stimulatory role in immune function. Subsets of dendritic cells were identified, each having its own surface markers. Dendritic cells were seen in the T-cell areas of organs of the lymph system, the ideal location for initiating immunity. Laboratories worldwide started to study dendritic cells and demonstrate their potent immune stimulatory functions.
Star performers
Dendritic cells exist throughout the body. As seen in the tissues of skin, airway, and lymphoid organs, the cells are shaped like stars.
When isolated and spun onto slides, they display numerous fine branches. When looked at with an electron microscope, these branches are long and thin and can appear spiny or sheet-like. When alive and viewed by phase-contrast microscopy, dendritic cells extend large, delicate, sheet-like processes that can drape around the cell bodies of lymphocytes, which can bind to dendritic cells in large numbers.
The processes of dendritic cells continually form, bend, and retract. The tentacular shape and constant movement of dendritic cells fit precisely with their functions: to snatch invaders, embrace other cells of the immune system, and deliver the antigens and other signals that are needed to initiate vigorous responses.
Dendritic cells are found in lymphoid or immune organs, and at the interfaces between our bodies and the environment. The epidermal layer of the skin has a rich network of dendritic cells, which were first described in 1868 by a medical student in Germany, Paul Langerhans, who thought they were part of the nervous system.
In addition, dendritic cells line the surfaces of the airway and intestine, where they function as sentinels that sample proteins and particulates from the environment. It took until 1973 for Ralph Steinman and Zanvil Cohn to begin the modern era of dendritic cell science by showing that dendritic cells are a new class of white blood cells with a number of distinctive features and functions.
Dendritic cells arise from proliferating progenitors, primarily in the bone marrow, a process driven by chemical messengers, to become precursors such as the monocytes in blood, and these in turn give rise to immature dendritic cells.
The cells develop further or mature as they capture, process antigens, and migrate under the influence of other chemical messengers to tissues such as spleen and lymph nodes. There they attract and stimulate T and B cells to produce strong immune responses.
The dendritic cells die unless they receive signals from the activated T cells to prolong their life span. These previously unknown cells are now recognised as controllers that both create and curtail immunity.
In the steady state, and when the body is challenged by injury and infection, dendritic cells travel from body surfaces to immune or lymphoid tissues, where they home to regions rich in T cells. There, dendritic cells deliver two types of information: they display antigens, the substances that are recognised by T cells, and they alert these lymphocytes to the presence of injury or infection.
This directs the T cells to make an immune response that is matched to the challenge at hand.
Orchestrating immunity
Dendritic cells are a critical, and previously missing, link in the immune system. As sentinels, dendritic cells patrol the body seeking out foreign invaders, whether these are bacteria, viruses, or dangerous toxins.
After capturing the invaders, often termed antigens, dendritic cells convert them into smaller pieces and display the antigenic fragments on their cell surfaces.
The dendritic cells then travel to lymph nodes or the spleen where they stimulate other cells of the immune system to make vigorous responses, in particular, the B cells that make antibodies to neutralise the invaders, and killer T cells that launch specific attacks to destroy them.
New research is showing that dendritic cells are equally responsible for a seemingly opposite role in health called immune tolerance, which silences dangerous immune cells and prevents them from attacking innocuous materials in the body or the body’s own tissues.
Given these functions of dendritic cells, it is not surprising that they are the subject of much research in medicine. During infection and cancer, microbes and tumours exploit dendritic cells to evade immunity, but dendritic cells can also capture infection- and tumour-derived protein and lipid antigens and generate resistance, including new strategies for vaccines.
During allergy, autoimmunity and transplantation, dendritic cells instigate unwanted innate and adaptive responses that cause disease, but dendritic cells also can suppress these conditions.
In other words, dendritic cells, because they orchestrate innate and adaptive immune responses, are an unavoidable target in studying disease and in designing treatments.
Studies of immunology and disease have long focused on antigens and lymphocytes (B cells, T cells, NK cells) as the mediators of immune responses. However, accumulating evidence shows that dendritic cells provide vital links between antigens and all types of lymphocytes.
Migration of dendritic cells
Before dendritic cells can perform their major function – to initiate the immune response – two events typically need to take place, migration and maturation.
Most dendritic cells circulate in the body in an “immature” state and lack many features that lead to a strong T-cell response. Immature dendritic cells are, nonetheless, ideally poised and well equipped to capture microbes and other sources of antigens.
Dendritic cells are stationed at surfaces where antigens gain access to the body. For example, they are positioned in the skin, where they are termed Langerhans cells. There, dendritic cells are involved with two of the body’s most powerful immune responses, organ transplantation and contact allergy.
Dendritic cells are also located in lymphatic vessels, which allow cells to move from peripheral tissues to lymphoid organs. There, they can encounter immune lymphocytes, selecting those cells that specifically recognise the antigens being carried by the dendritic cells.
At this point, the immune response begins. The lymphocytes begin to grow vigorously and they start to produce products that will serve to eliminate infections and other sources of antigens.
Initiating the immune response
Dendritic cells are professional antigen processing cells. They have a number of receptors that enhance the uptake of antigens, and they are specialised to convert these antigens into complexes that can be recognised by lymphocytes.
However, the dendritic cells need to do more than present antigens to T cells. They are also potent accessory cells that directly trigger and control responses by T cells and by all other types of lymphocytes.
Some early studies showed that dendritic cells carry on their surface high levels of major histocompatibility complex (MHC) products, which are critically recognised by T-lymphocytes. The high levels of MHC led Steinman to test these cells in the mixed leukocyte reaction (MLR), a well-known clinical assay for identifying the compatibility of tissue transplants between donors and recipients.
At the time, this assay was known as mixed “lymphocyte” reaction, because it presumed that the B lymphocytes were presenting MHC products from the organ transplant donor to the recipient’s T cells.
Instead, Steinman found that dendritic cells were the major stimulators and were unusually potent. In fact, a dendritic cell to T cell ratio of one to 100 sufficed to initiate vigorous and optimal responses.
Moreover, the dendritic cells directly activated both the subset of helper T cells as well as the killer T cells. Once activated by dendritic cells, the T cells could also interact vigorously with other antigen-presenting B cells and macrophages to produce additional immune responses from these cells.
The term “accessory” has since been replaced by the terms “professional” and “co-stimulatory”, but the basic concept is unchanged. Dendritic cells provide the T cells with needed accessory or co-stimulatory substances, in addition to giving them a signal to begin to grow and function.
Dendritic cells also influence the type or quality of the response. A T cell, for example, has to know whether the enemy is a virus that needs to be resisted with its own interferons and cytolytic molecules, or whether the pathogen is a parasite that requires a different set of protective cells to respond with antibodies.
Therefore, when dendritic cells migrate to the body’s pool of T cells areas in the lymph nodes, they need to orchestrate two fundamental components from the repertoire of lymphocyte functions.
First the dendritic cells select the specific T cells from the assembled repertoire that recognise the specific peptide information the dendritic cells are carrying. Amazingly, only one in 10,000-100,000 of the T cells in that repertoire are able to respond to this information.
Second, the rare T cells that are selected for expansion then differentiate into helper and killer T cells that have the appropriate functions to eliminate the infection or disease-causing stimulus.
After these two decisions have been made, the newly activated T cells leave the lymph node to return to the body surface or peripheral organ to eliminate the antigens.
For orchestrating these various processes efficiently and precisely, the dendritic cells are considered to be “conductors of the immune orchestra”.
Dendritic cells and immune tolerance
Most studies have focused on the dendritic cells’ role in activating T cells to resist foreign antigens, especially infections.
Recent research in Steinman’s laboratory, in close collaboration with other laboratories at Rockefeller, is showing that dendritic cells can also make the immune system tolerate harmless antigens, including those from the body’s own tissues, cells, and proteins. This is necessary to keep the body from making an immune attack on itself.
The dendritic cell system appears to play a pivotal role in two kinds of immune tolerance. Usually, when young T cells are launched from the thymus, the dendritic cells participate in eliminating those cells bearing “self-reactive antigens” before they can harm the body’s own tissues, a mechanism known as central tolerance.
Since some T cells may slip through this process, or other self-antigens do not access the thymus, or still others arise later in life, the dendritic cells also participate in the mechanism known as peripheral tolerance that restrains their activity.
In the absence of infection or inflammation, the dendritic cells are in an immature state, but they are not quiescent. Like perpetual custodians, they clean house and collect trash.
Sweeping non-stop through tissues and into lymphoid organs, the dendritic cells capture all kinds of antigens – the harmless self-antigens, those from dying cells, and the many non-pathogenic antigens encountered from the environment.
Two mechanisms have been identified that allow dendritic cells to induce tolerance. The antigen-loaded immature dendritic cells silence T cells by either deleting them or by inducing regulatory T cells that suppress the reactions of other immune cells.
When the dendritic cells subsequently mature in response to infection, the pre-existing tolerance nullifies any reaction to innocuous antigens and allows the dendritic cells to focus the immune response on the pathogen.
Other current research is providing clues about the dendritic cells’ occasional failures to maintain tolerance. Failure to silence the immune system can lead to autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis.
If dendritic cells are too tolerant, this can create a permissive environment for chronic infectious agents, such as HIV. Infections and tumours can exploit the tolerogenic function of dendritic cells, shut down the normal immune defenses, and perpetuate disease.
References:
1. Steinman, R.M., and H. Hemmi. 2006. Dendritic cells: translating innate to adaptive immunity. In Innate Imunity to Imunological Memory. eds Pulendran, B., and R. Ahmed, Current Topics in Microbiology and Immunology. 311, 17-58. (Berlin Heidelberg: Springer-Verlag).
2. Silverstein, S.C., Steinman, R.M., and Cohn, Z.A. Endocytosis (review). Ann. Rev. Biochem. 46: 669-722, 1977.
3. Steinman, R.M., and Nussenzweig, M.C. Dendritic cells: features and functions (review). Immun. Rev. 53: 127-147, 1980.
4. Steinman, R.M. Dendritic cells (review). Transplant. 31: 151-155, 1981.
5. Tew, J.G., Thorbecke, J., and Steinman, R.M. Dendritic cells in the immune response: characteristics and recommended nomenclature. J. Reticuloendothelial Soc. 31: 371-380, 1982.
DENDRITIC cells were discovered in 1973 by Ralph Steinman and Zanvil A. Cohn at the Rockefeller University. At the time, Steinman and Cohn were studying spleen cells to understand the induction of immune responses in a major lymphoid organ of the mouse.
They were aware from research in other laboratories that the development of immunity by mouse spleen required both lymphocytes and “accessory cells”, which were of uncertain identity and function. The accessory cells were thought to be typical macrophages (a type of white blood cell that engulfs and digests cellular debris and pathogens), but despite extensive laboratory experience with macrophages, Steinman and Cohn encountered a population of cells with unusual shapes and movements that had not been seen before. Because the cells had unusual tree-like or “dendritic” processes, Steinman named them “dendritic cells”
.
When Steinman evaluated this population of cells, they had little, if any, resemblance to the well-known macrophages. Accordingly, these cells were identified as novel cells having distinct properties, and eventually, functions.
 |
| Laboratories worldwide have studied dendritic cells and demonstrated their potent immune stimulatory functions. |
Star performers
Dendritic cells exist throughout the body. As seen in the tissues of skin, airway, and lymphoid organs, the cells are shaped like stars.
When isolated and spun onto slides, they display numerous fine branches. When looked at with an electron microscope, these branches are long and thin and can appear spiny or sheet-like. When alive and viewed by phase-contrast microscopy, dendritic cells extend large, delicate, sheet-like processes that can drape around the cell bodies of lymphocytes, which can bind to dendritic cells in large numbers.
The processes of dendritic cells continually form, bend, and retract. The tentacular shape and constant movement of dendritic cells fit precisely with their functions: to snatch invaders, embrace other cells of the immune system, and deliver the antigens and other signals that are needed to initiate vigorous responses.
Dendritic cells are found in lymphoid or immune organs, and at the interfaces between our bodies and the environment. The epidermal layer of the skin has a rich network of dendritic cells, which were first described in 1868 by a medical student in Germany, Paul Langerhans, who thought they were part of the nervous system.
In addition, dendritic cells line the surfaces of the airway and intestine, where they function as sentinels that sample proteins and particulates from the environment. It took until 1973 for Ralph Steinman and Zanvil Cohn to begin the modern era of dendritic cell science by showing that dendritic cells are a new class of white blood cells with a number of distinctive features and functions.
Dendritic cells arise from proliferating progenitors, primarily in the bone marrow, a process driven by chemical messengers, to become precursors such as the monocytes in blood, and these in turn give rise to immature dendritic cells.
The cells develop further or mature as they capture, process antigens, and migrate under the influence of other chemical messengers to tissues such as spleen and lymph nodes. There they attract and stimulate T and B cells to produce strong immune responses.
The dendritic cells die unless they receive signals from the activated T cells to prolong their life span. These previously unknown cells are now recognised as controllers that both create and curtail immunity.
In the steady state, and when the body is challenged by injury and infection, dendritic cells travel from body surfaces to immune or lymphoid tissues, where they home to regions rich in T cells. There, dendritic cells deliver two types of information: they display antigens, the substances that are recognised by T cells, and they alert these lymphocytes to the presence of injury or infection.
This directs the T cells to make an immune response that is matched to the challenge at hand.
Orchestrating immunity
Dendritic cells are a critical, and previously missing, link in the immune system. As sentinels, dendritic cells patrol the body seeking out foreign invaders, whether these are bacteria, viruses, or dangerous toxins.
After capturing the invaders, often termed antigens, dendritic cells convert them into smaller pieces and display the antigenic fragments on their cell surfaces.
The dendritic cells then travel to lymph nodes or the spleen where they stimulate other cells of the immune system to make vigorous responses, in particular, the B cells that make antibodies to neutralise the invaders, and killer T cells that launch specific attacks to destroy them.
New research is showing that dendritic cells are equally responsible for a seemingly opposite role in health called immune tolerance, which silences dangerous immune cells and prevents them from attacking innocuous materials in the body or the body’s own tissues.
 |
| The use of dendritic cells in cancer treatment is an example of the impact of Steinman’s discovery. |
During allergy, autoimmunity and transplantation, dendritic cells instigate unwanted innate and adaptive responses that cause disease, but dendritic cells also can suppress these conditions.
In other words, dendritic cells, because they orchestrate innate and adaptive immune responses, are an unavoidable target in studying disease and in designing treatments.
Studies of immunology and disease have long focused on antigens and lymphocytes (B cells, T cells, NK cells) as the mediators of immune responses. However, accumulating evidence shows that dendritic cells provide vital links between antigens and all types of lymphocytes.
Migration of dendritic cells
Before dendritic cells can perform their major function – to initiate the immune response – two events typically need to take place, migration and maturation.
Most dendritic cells circulate in the body in an “immature” state and lack many features that lead to a strong T-cell response. Immature dendritic cells are, nonetheless, ideally poised and well equipped to capture microbes and other sources of antigens.
Dendritic cells are stationed at surfaces where antigens gain access to the body. For example, they are positioned in the skin, where they are termed Langerhans cells. There, dendritic cells are involved with two of the body’s most powerful immune responses, organ transplantation and contact allergy.
Dendritic cells are also located in lymphatic vessels, which allow cells to move from peripheral tissues to lymphoid organs. There, they can encounter immune lymphocytes, selecting those cells that specifically recognise the antigens being carried by the dendritic cells.
At this point, the immune response begins. The lymphocytes begin to grow vigorously and they start to produce products that will serve to eliminate infections and other sources of antigens.
Initiating the immune response
Dendritic cells are professional antigen processing cells. They have a number of receptors that enhance the uptake of antigens, and they are specialised to convert these antigens into complexes that can be recognised by lymphocytes.
However, the dendritic cells need to do more than present antigens to T cells. They are also potent accessory cells that directly trigger and control responses by T cells and by all other types of lymphocytes.
Some early studies showed that dendritic cells carry on their surface high levels of major histocompatibility complex (MHC) products, which are critically recognised by T-lymphocytes. The high levels of MHC led Steinman to test these cells in the mixed leukocyte reaction (MLR), a well-known clinical assay for identifying the compatibility of tissue transplants between donors and recipients.
At the time, this assay was known as mixed “lymphocyte” reaction, because it presumed that the B lymphocytes were presenting MHC products from the organ transplant donor to the recipient’s T cells.
Instead, Steinman found that dendritic cells were the major stimulators and were unusually potent. In fact, a dendritic cell to T cell ratio of one to 100 sufficed to initiate vigorous and optimal responses.
Moreover, the dendritic cells directly activated both the subset of helper T cells as well as the killer T cells. Once activated by dendritic cells, the T cells could also interact vigorously with other antigen-presenting B cells and macrophages to produce additional immune responses from these cells.
The term “accessory” has since been replaced by the terms “professional” and “co-stimulatory”, but the basic concept is unchanged. Dendritic cells provide the T cells with needed accessory or co-stimulatory substances, in addition to giving them a signal to begin to grow and function.
Dendritic cells also influence the type or quality of the response. A T cell, for example, has to know whether the enemy is a virus that needs to be resisted with its own interferons and cytolytic molecules, or whether the pathogen is a parasite that requires a different set of protective cells to respond with antibodies.
Therefore, when dendritic cells migrate to the body’s pool of T cells areas in the lymph nodes, they need to orchestrate two fundamental components from the repertoire of lymphocyte functions.
First the dendritic cells select the specific T cells from the assembled repertoire that recognise the specific peptide information the dendritic cells are carrying. Amazingly, only one in 10,000-100,000 of the T cells in that repertoire are able to respond to this information.
Second, the rare T cells that are selected for expansion then differentiate into helper and killer T cells that have the appropriate functions to eliminate the infection or disease-causing stimulus.
After these two decisions have been made, the newly activated T cells leave the lymph node to return to the body surface or peripheral organ to eliminate the antigens.
For orchestrating these various processes efficiently and precisely, the dendritic cells are considered to be “conductors of the immune orchestra”.
Dendritic cells and immune tolerance
Most studies have focused on the dendritic cells’ role in activating T cells to resist foreign antigens, especially infections.
Recent research in Steinman’s laboratory, in close collaboration with other laboratories at Rockefeller, is showing that dendritic cells can also make the immune system tolerate harmless antigens, including those from the body’s own tissues, cells, and proteins. This is necessary to keep the body from making an immune attack on itself.
The dendritic cell system appears to play a pivotal role in two kinds of immune tolerance. Usually, when young T cells are launched from the thymus, the dendritic cells participate in eliminating those cells bearing “self-reactive antigens” before they can harm the body’s own tissues, a mechanism known as central tolerance.
Since some T cells may slip through this process, or other self-antigens do not access the thymus, or still others arise later in life, the dendritic cells also participate in the mechanism known as peripheral tolerance that restrains their activity.
In the absence of infection or inflammation, the dendritic cells are in an immature state, but they are not quiescent. Like perpetual custodians, they clean house and collect trash.
Sweeping non-stop through tissues and into lymphoid organs, the dendritic cells capture all kinds of antigens – the harmless self-antigens, those from dying cells, and the many non-pathogenic antigens encountered from the environment.
Two mechanisms have been identified that allow dendritic cells to induce tolerance. The antigen-loaded immature dendritic cells silence T cells by either deleting them or by inducing regulatory T cells that suppress the reactions of other immune cells.
When the dendritic cells subsequently mature in response to infection, the pre-existing tolerance nullifies any reaction to innocuous antigens and allows the dendritic cells to focus the immune response on the pathogen.
Other current research is providing clues about the dendritic cells’ occasional failures to maintain tolerance. Failure to silence the immune system can lead to autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis.
If dendritic cells are too tolerant, this can create a permissive environment for chronic infectious agents, such as HIV. Infections and tumours can exploit the tolerogenic function of dendritic cells, shut down the normal immune defenses, and perpetuate disease.
References:
1. Steinman, R.M., and H. Hemmi. 2006. Dendritic cells: translating innate to adaptive immunity. In Innate Imunity to Imunological Memory. eds Pulendran, B., and R. Ahmed, Current Topics in Microbiology and Immunology. 311, 17-58. (Berlin Heidelberg: Springer-Verlag).
2. Silverstein, S.C., Steinman, R.M., and Cohn, Z.A. Endocytosis (review). Ann. Rev. Biochem. 46: 669-722, 1977.
3. Steinman, R.M., and Nussenzweig, M.C. Dendritic cells: features and functions (review). Immun. Rev. 53: 127-147, 1980.
4. Steinman, R.M. Dendritic cells (review). Transplant. 31: 151-155, 1981.
5. Tew, J.G., Thorbecke, J., and Steinman, R.M. Dendritic cells in the immune response: characteristics and recommended nomenclature. J. Reticuloendothelial Soc. 31: 371-380, 1982.
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