1 histórico das células dendríticas - primeira apresentação.pdf


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1 histórico das células dendríticas - primeira apresentação.pdf

  1. 1. Annu. Rev. Immunol. 2012.30. Downloaded from www.annualreviews.org by Universidade Federal do Amazonas on 03/21/12. For personal use only. IY30CH01-Steinman ARI 17 November 2011 12:14 Ralph M. SteinmanJanuary 14, 1943 – September 30, 2011
  2. 2. IY30CH01-Steinman ARI 17 November 2011 12:14 V I E W Review in Advance first E posted online R on November 17, 2011. S (Changes may still occur before final C E publication I N online and in print.) N A D V A Decisions About Dendritic Cells: Past, Present, and Future Ralph M. SteinmanAnnu. Rev. Immunol. 2012.30. Downloaded from www.annualreviews.orgby Universidade Federal do Amazonas on 03/21/12. For personal use only. Laboratory of Cell Physiology and Immunology, The Rockefeller University, New York, NY 10021 Annu. Rev. Immunol. 2012. 30:1–22 Keywords The Annual Review of Immunology is online at immunol.annualreviews.org adaptive immunity, antigen presentation, immunotherapy, adjuvants This article’s doi: Abstract 10.1146/annurev-immunol-100311-102839 A properly functioning adaptive immune system signifies the best fea- Copyright c 2012 by Annual Reviews. All rights reserved tures of life. It is diverse beyond compare, tolerant without fail, and capable of behaving appropriately with a myriad of infections and other 0732-0582/12/0423-0001$20.00 challenges. Dendritic cells are required to explain how this remarkable ∗ Photo credit: Zach Veilleux, The Rockefeller system is energized and directed. I frame this article in terms of the ma- University, August 21, 2007. jor decisions that my colleagues and I have made in dendritic cell science and some of the guiding themes at the time the decisions were made. As a result of progress worldwide, there is now evidence of a central role for dendritic cells in initiating antigen-specific immunity and tolerance. The in vivo distribution and development of a previously unrecognized white cell lineage is better understood, as is the importance of den- dritic cell maturation to link innate and adaptive immunity in response to many stimuli. Our current focus is on antigen uptake receptors on dendritic cells. These receptors enable experiments involving selective targeting of antigens in situ and new approaches to vaccine design in preclinical and clinical systems. 1
  3. 3. IY30CH01-Steinman ARI 17 November 2011 12:14 DECIDING TO STUDY role of accessory cells in immunity seemed to IMMUNOLOGY be a critical mystery to unravel. During this same period of training in As explained elsewhere (1, 2), I had the good medicine, a curious episode of fate involved fortune to grow up in Sherbrooke, Quebec, at- a so-called throwaway journal that medical tend McGill University in Montreal, and then students received gratis in their hospital study medicine at Harvard Medical School and mailboxes. An issue arrived that caught my Massachusetts General Hospital in Boston. All attention because it described the new field of along, my teachers made it fun to learn, per- cell-mediated immunity and how important it haps so much so that my decision to focus on could be for medicine. The throwaway article immunology did not emerge until the end of on cell-mediated immunity kept citing a series my education in medicine. Then I became fas- of early reviews for the new field in the British cinated with clonal selection theory by read- Medical Bulletin of 1965. ing Clonal Selection Theory of Acquired Immunity When I turned to that issue, Peter Medawar, (1959) by MacFarlane Burnet (3). The theory the father of transplantation, wrote, “We areAnnu. Rev. Immunol. 2012.30. Downloaded from www.annualreviews.orgby Universidade Federal do Amazonas on 03/21/12. For personal use only. tried to explain one of the hallmarks of the im- still generally ignorant of how a homograft re- mune system: its unique diversity and ability action starts” (7, p. 98). And James Gowans, to recognize determinants or antigens from a who discovered that lymphocytes are the medi- spectrum of infections, tumors, transplants, self ators of immunity, wrote, “Very little is known tissues, and allergens. Burnet envisaged an ele- about the way in which antigens from vascu- gant repertoire of clones, each with an antibody larized grafts reach the lymphoid cells of the receptor specific for one antigen; immunization host” (8, p. 107). How could there be uncer- required an initial selection step by the antigen tainty about the initiation of the most power- binding to its receptor. One of the amazing tri- ful immune response in the body, when all that umphs of immunology during my subsequent seemed necessary was for the foreign antigens career was to see Burnet’s repertoire unraveled on transplants to select clones with receptors through discoveries of how adaptive T and B specific to these determinants? cells are formed, each expressing a single recep- Deciding how to approach this problem was tor and together an unparalleled diverse library something I struggled with for two years be- of specificities. fore beginning my postdoctoral experiments. During medical training in the late 1960s, In contrast, it was not a struggle to decide I attended a late afternoon set of seminars in that I needed to work with Zanvil Cohn and modern immunology organized by Kurt Bloch James Hirsch at The Rockefeller University. at Massachusetts General Hospital. One of They were leaders in the modern cell biology the lectures described that macrophages were of phagocytes, and these were the cells deemed accessories needed to initiate immunity. We to be critical accessories to initiate immunity. were taught that when a macrophage takes Fortunately, I gained a position in their Lab- up an antigen, an immunogenic RNA-antigen oratory of Cellular Physiology and Immunol- complex is formed, and this instructed immune ogy. When I began my postdoctoral research, cells to start making a specific antibody (4–6). I did not have a hypothesis that a new cell type This was my first exposure to the idea that must exist to understand how immunity begins. clonal selection is not straightforward to Rather, I had a commitment to what I thought initiate; somehow antigen has to interact was a major problem: How does the body de- with RNA from a macrophage. The scenario cide to make an immune response, especially seemed hard to believe given what was already a cell-mediated one, when antigen enters the known about subcellular compartments and body? Or to put it another way, how is Burnet’s their membrane barriers. Nevertheless, the selection of T cell clones initiated? 2 Steinman
  4. 4. IY30CH01-Steinman ARI 17 November 2011 12:14 The decision to emphasize problems that appear central to medicine is something I will Medical conditions to which the immune system contributes never abandon, and, of course, I am not alone in this. The relevance of immunology to so many disease states (Figure 1) is not something one Transplantation Allergies and asthma just mentions in a search for grant funds. In- stead, it is a thrilling driving force for choosing Cancer Autoimmunity: • Juvenile diabetes which experiments and experimental systems to Infections, • Multiple sclerosis pursue. I dislike the much-used distinction be- e.g., AIDS • Inflammatory bowel tween basic and clinical immunology. Research disease on diseases and in patients are both basic. For Atherosclerosis Bone disease example, the simultaneous discovery of TNF by Anthony Cerami at Rockefeller and Lloyd T cells Old at Memorial Sloan Kettering Cancer Center was fundamental, but was it not equallyAnnu. Rev. Immunol. 2012.30. Downloaded from www.annualreviews.orgby Universidade Federal do Amazonas on 03/21/12. For personal use only. basic for Marc Feldmann and Ravinder Maini Figure 1 in London to make the shocking discovery The immune system contributes to various medical conditions, either to that anti-TNF antibodies were able to block protect against disease, including with vaccination and immune therapies, or to severe inflammatory diseases in people with contribute to pathology and symptoms. At the bottom of the figure are areas being studied more recently for their immune involvements: atherosclerosis rheumatoid arthritis? The word “translational” and bone disease. All these conditions either are becoming more frequent or, in can be helpful in one sense, by indicating to our the case of a disease such as cancer, are decreasing very little. Also, new community of supporters that we are studying infections always evolve, most notably AIDS, which was not known when I disease and often patients. But too often the began my career. term implies that medical progress comes from a simple translation or implementation of basic It was invaluable that Zanvil Cohn and all studies and that research with patients and the scientists in the lab had a rich experience pathogens is not part of the discovery equation. with macrophage biology. This provided a This is untrue. Research attempts to uncover huge boost to work out that dendritic cells are the unknown, whether it is clinical, cellular, or entirely different from macrophages, even if molecular (Figure 1). others at the time did not agree. Also critical was that The Rockefeller University was the birthplace of many discoveries in modern cell biology and subcellular structure. David DISCOVERING A NEW Sabatini’s glutaraldehyde fixation method used CELL TYPE for electron microscopy and cytochemistry The route to identifying dendritic cells was not preserved dendritic cells in their distinctive direct (1, 2). The key decision was to examine form, which was similar to what we observed in the spleen and move away from the peritoneal the living state by phase contrast microscopy. cavity, which remains a focus of macrophage re- Other major breakthroughs in cell biology were search. Others had shown that spleen cell sus- the identification of lysosomes by Christian de pensions are special because they can be used Duve (12) and the elegant mechanisms from to study the initiation of antibody responses in Cohn, Hirsch, and colleagues (13) on uptake culture (9). But why? Once we looked at the and delivery of particles to digestive lysosomes spleen cells, we quickly observed novel cells, in macrophages. It was quickly shown that dendritic cells as we called them, and began to dendritic cells have few standard lysosomes by try to understand them. They did not look like morphology or acid phosphatase staining, and macrophages, and this was soon reinforced with phagocytosis was tough to demonstrate. These more functional distinctions (10, 11). cells were unusual. www.annualreviews.org • Decisions on Dendritic Cells 3
  5. 5. IY30CH01-Steinman ARI 17 November 2011 12:14 By 1978, eight years after beginning re- or antibody complexes to the newly recognized search at Rockefeller, I still had the impor- dendritic cells. tant problem of elucidating how immunity is In fact, it took almost five years of ef- initiated. I was aware of a cell type that did fort, largely on cultures that allowed the mas- not look like or behave like any monocyte or sive expansion of antibody-forming cells (19), macrophage that had been encountered. I en- to decide to study the in vitro counterpart joyed the unshakable patience and wisdom of of Medawar’s transplant rejection, the mixed Zanvil Cohn. I could identify the distinct den- leukocyte reaction (MLR) (20). The dendritic dritic cell by its unusual cell shape and or- cells proved to be the principal and surpris- ganelles so that I could eventually purify it. ingly potent stimulator cells, whereas MHC- Then I observed its high expression of major bearing macrophages and B cells were weak. histocompatibility complex (MHC) molecules It took another five years for Robert Lech- with effective antibodies that had just become ler and Richard Batchelor in London to re- available, and I began to assay function (14). port that dendritic cells are unique inducers of I wonder whether I could succeed today transplant rejection in vivo (21). During theseAnnu. Rev. Immunol. 2012.30. Downloaded from www.annualreviews.orgby Universidade Federal do Amazonas on 03/21/12. For personal use only. in obtaining my first grant, AI13013, now slow early years, I benefited from essential sup- in its 36th year, to pursue these dendritic port from the Leukemia Society of America, the cells. Many funding sources provide research American Heart Association, and the Irma T. support almost exclusively on the basis of the Hirschl Fund, and again, I had the unique en- specifics and feasibility of what one plans to couragement of Zanvil Cohn. Then in the late do. Research funding should instead prioritize 1970s, after the initial years of struggle, the individuals who have done special groundwork pace changed markedly when I was joined by and want to use their discoveries to pursue an PhD students Michel Nussenzweig and Wes important problem. In other words, funding van Voorhis, and by Kayo Inaba, fresh from her should be determined by what the investigator PhD in Kyoto. brings to the table from his or her past work and the importance of the problem he or she chooses to study. It is simply illogical DISSECTING THE AFFERENT to award funds for a feasible and detailed AND EFFERENT LIMBS OF future approach, in which case the biological CELL-MEDIATED IMMUNITY unknown is likely doomed to be incremental. As mentioned, the first functional assays we In writing my first grant, even after spotting used to identify the immune-initiating function unusual cells, I could not have hypothesized that of dendritic cells did not involve the addition of dendritic cells would prove to be unique ini- antigens that needed to be processed. Instead, tiators of immunity. In the early 1970s, there we used responses in the MLR, a reaction in were several possible roles for “accessory cells,” which T cells largely recognize endogenous one being the retention of intact antigen, par- peptides complexed to the foreign MHC. A ticularly immune complexes on the cell sur- similar situation took place in the laboratories face. This was observed in vivo on “dendritic of William Bowers and Jon Austyn, who macrophages” (now called follicular dendritic observed the potent accessory function of cells, FDCs) (15). I did manage to show with dendritic cells relative to other cell types using Lei Chen that persistence in vivo is truly on the a polyclonal mitogenesis assay in which T cell surface of the FDC (16, 17). This meant that cells were treated with sodium periodate (22, FDCs are very different from macrophages, on 23). But then we began to move forward with which I had failed previously to show retention immunity to specific added antigens (still the of intact antigen and immune complexes in spite focus of the lab), for which the reactive T cell of large amounts of endocytosis (18). But I was clones are rare. However, we were not initially also unable to show binding of intact antigen thinking of antigen processing to produce 4 Steinman
  6. 6. IY30CH01-Steinman ARI 17 November 2011 12:14 peptide MHC products. This was unraveled interact vigorously with the antigen-specific only later from the work of many other and MHC-restricted T blasts that are first in- investigators, particularly Emil Unanue, Alain duced by dendritic cells (30, 31). James Young, Townsend, Jack Strominger, Don Wiley, and Sumi Koide, and Jon Austyn extended this two- Pam Bjorkman. step mechanism to other assays for successful Nonetheless, dendritic cells were quickly T cell responses (23, 32, 33). shown to effectively present complex antigens The experiments led by Inaba were long to T cells. Nussenzweig demonstrated that lasting in two respects, as summarized in later dendritic cells present exogenous antigen to reviews on the importance of dendritic cells T cells in an MHC-restricted fashion and in immunogenicity (34, 35). First, dendritic that they induce specific cytolytic T cell re- cells are not simply antigen-presenting cells sponses (24). He co-cultured the dendritic cells but, in addition, are specialized accessories for with T cells, irradiated trinitrophenyl (TNP)- initiating immunity. All cells that express MHC modified thymocytes, and found that the T cells molecules can use these to present antigen— developed MHC-restricted cytolytic activity. but primarily to activated T cells. Second, weAnnu. Rev. Immunol. 2012.30. Downloaded from www.annualreviews.orgby Universidade Federal do Amazonas on 03/21/12. For personal use only. Although not appreciated at the time, this was proposed an in vivo counterpart for the findings also the first demonstration of “cross-priming” with cell clusters, based on several prior sets of by dendritic cells. Wes van Voorhis showed observations: that immune responses begin in that human blood contains dendritic cells simi- lymphoid organs; that T blasts pour into the lar to the ones we had found in mice (25), and he thoracic duct lymph from lymphoid tissues sev- studied presentation of Candida to proliferating eral days after the onset of an immune response; T cells. Inaba, as she had begun to do during her and that the main place that dendritic cells can PhD (26), analyzed a system employing sheep be found is in T cell zones (36). Therefore, we red blood cells, a classical antigen at the time to envisaged that dendritic cells would initiate the study helper T cell function in antibody forma- “afferent limb” of immunity by presenting anti- tion (27). In all these systems, small numbers of gen in the T cell areas of lymphoid tissues in dendritic cells elicited a T cell response, while vivo, and later the activated T cells would leave much larger numbers of other cell types were via the lymph, enter the thoracic duct and then inactive. Early reviews emphasized the features the blood, and finally reach the inflamed tissues of this newly uncovered lineage of white cells to bring about the efferent or effector limb of (28, 29). immunity. These findings made us want to understand These early assays, as well as the antigens what the MHC is doing when expressed on that dominated research in immunology at the other cell types. Inaba and I decided to study time, may seem remote to younger readers, but distinct cell clusters—5–10 cells in width— the underlying themes live on. In particular, the which we routinely observed in our cultures availability of dendritic cells makes it possible when dendritic cells were initiating immunity. to initiate immunity with intact specific anti- The clusters contained most of the dendritic gens. It was not necessary to focus on prepro- cells in the culture, and these were bound to cessed peptides and various mitogens. With- lymphocytes. The clusters proved to be the out knowing about antigen processing, we were sites for the onset of lymphocyte prolifera- finding that dendritic cells were carrying out tion or “blastogenesis,” but then the responding the two series of events needed for T cells to “blasts” moved away from the cluster. When start their protective and pathogenic functions, purified, the primed T cells showed responses i.e., dendritic cells allowed T cells to recognize to other cell types presenting antigen. For ex- antigen (later peptide MHC complexes) and to ample, Inaba found that B cells fail to initiate respond to it (later accessory or costimulatory T cell immunity to a soluble protein but could functions). www.annualreviews.org • Decisions on Dendritic Cells 5
  7. 7. IY30CH01-Steinman ARI 17 November 2011 12:14 Table 1 International symposia on dendritic cells in fundamental and clinical immunology City Date Organizers I Yamagata City, Japan June 1990 Y. Imai II Amsterdam, Holland June 1992 E.C.M. Hoefsmit, P. Nieuwenhuis, E.W.A. Kamperdijk, A.C. Dijkstra III Annecy, France October 1994 J. Banchereau, D. Schmitt, L. Valette IV Venice, Italy October 1996 P. Riccardi-Castagnoli, G. Girolomoni, A. Lanzavecchia V Pittsburgh, USA September 1998 M. Lotze, J. Banchereau, R. Steinman VI Port Douglas, Australia May 2000 K. Shortman, D. Hart, P. Holt, P. Wood VII Bamberg, Germany September 2002 G. Schuler, A. Steinkasserer, G. Stingl VIII Bruges, Belgium October 2004 M. Moser, K. Thielemans, T. Boon IX Edinburgh, Scotland September 2006 G. MacPherson, J. Liversidge, J. Austyn X Kobe, Japan October 2008 M. Furue, K. Inaba, S. Okyasu,Annu. Rev. Immunol. 2012.30. Downloaded from www.annualreviews.orgby Universidade Federal do Amazonas on 03/21/12. For personal use only. K. Matsushima XI Lugano, Switzerland September 2010 A. Lanzavecchia, M.G. Manz, F. Sallusto XII Daegu, South Korea October 2012 H-Y. Kim, Y-S. Bae, C-K. Lee A relatively small but international commu- TRACING THE DEVELOPMENT nity was actively contributing to dendritic cell OF DENDRITIC CELLS: THEIR research in fundamental and clinical immunol- MATURATION AND ogy in the 1980s. Sizeable international biennial DERIVATION FROM BONE meetings dedicated to this theme began in 1990 MARROW PROGENITORS (Table 1) and in alternating years at Keystone Understanding development is essential to Symposia in the United States (Table 2). The defining a cell lineage. Our first experiments organizers of these conferences include many in this sphere came through a decision by of the leaders in dendritic cell biology over the Gerold Schuler from Innsbruck to join our lab years. Nevertheless, before the early 1990s, to determine how epidermal Langerhans cells dendritic cells were not really on the main relate to spleen dendritic cells. He discovered stage of immunology. This was largely because what we termed dendritic cell maturation immunology was profitably absorbed with the (37). We prefer the term “maturation” to crucial understanding of MHC restriction, “activation” because the latter typically refers antigen processing and presentation, and the to an on-off event or restricted series of events, T cell receptor. These events could be studied, whereas what we were observing was the at least initially, with already immunized large-scale differentiation of a cell lineage, T cells and T cell lines, clones, and hybrido- which is called maturation when, for example, mas. Isolating dendritic cells for this kind myelocytes become neutrophils or normoblasts of antigen presentation research was not become red cells. Dendritic cell maturation is critical initially. But today, direct attention to the critical link between innate and adaptive dendritic cells is valuable for many mechanistic T cell–dependent immunity. studies, e.g., antigen uptake and presentation; The concept is that dendritic cells respond the links between innate and adaptive immu- quickly to environmental changes and dif- nity; T cell differentiation; dynamics of the ferentiate extensively to become mature or immune system in situ; stimulation of other immunogenic accessory cells. Microbes are not lymphocytes, especially NK cells; and clinical the only sources of these stimuli. There are immunology. many other sources, including the two most 6 Steinman
  8. 8. IY30CH01-Steinman ARI 17 November 2011 12:14 Table 2 Keystone Symposia on dendritic cells Year and place Symposium title Organizers 1995 Dendritic Cells: Antigen Presenting Cells of T Jacques Banchereau and Ralph Steinman Taos, NM and B Lymphocytes 1998 Cellular and Molecular Biology of Dendritic Ralph Steinman, Michel Nussenzweig, and Santa Fe, NM Cells Jacques Banchereau 2001 Dendritic Cells: Interfaces with Ralph M. Steinman, Anne O’Garra, and Jacques Taos, NM Immunobiology and Medicine Banchereau 2003 Dendritic Cells: Interfaces with Ralph M. Steinman, Anne O’Garra, and Jacques Keystone, CO Immunobiology and Medicine Banchereau Joint with Cell Biology of the Immune Response Ira Mellman, Richard Flavell, and Ralph M. Steinman 2005 Dendritic Cells at the Center of Innate and Anne O’Garra, Jacques Banchereau, and Alan Sher Vancouver, BC Adaptive Immunity: Eradication of Pathogens and Cancer and Control of ImmunopathologyAnnu. Rev. Immunol. 2012.30. Downloaded from www.annualreviews.orgby Universidade Federal do Amazonas on 03/21/12. For personal use only. 2007 Intracellular and Intercellular Signaling in Muriel Moser, Caetano Reis e Sousa, and Keystone, CO Dendritic Cell Function Yong-Jun Liu Joint with Imaging Immune Responses Ronald N. Germain and Ellen A. Robey 2009 Dendritic Cells Giorgio Trinchieri, Gwendalyn J. Randolph, and Banff, Alberta Sebastian Amigorena Joint with Pattern Recognition Molecules and Immune Jenny P. Ting, Richard A. Flavell, and Luke A.J. Sensors of Pathogens O’Neill 2011 Dendritic Cells and the Initiation of Adaptive Ira Mellman, Michel C. Nussenzweig, Virginia Santa Fe, NM Immunity Pascual, and Federica Sallusto Joint with Cancer Control by Tumor Suppressors and Laurence Zitvogel, Anna Karolina Palucka, and Immune Effectors (Tumor Immunology) Mark J. Smyth 2013 Understanding Dendritic Cell Biology to Miriam Merad and Bart Lambrecht Venue to be determined Improve Human Disease powerful settings for cell-mediated immunity, maturation stimulus to trigger endosomal acid- graft rejection and contact hypersensitivity, ification (40) and thereby the catabolism of pro- which take place in ostensibly nonmicrobial tein antigens and the MHCII-associated invari- settings. Maturation occurs whenever epider- ant chain. These two key steps are required to mal dendritic cells, and spleen dendritic cells in allow peptide-MHCII complexes to form inside later experiments, are placed in culture. Maggi the endocytic system, followed by their subse- Pack found that one critical factor for the mat- quent display at the cell surface (41, 42). More uration of Langerhans cells was GM-CSF (38). research is needed, but the endocytic system— The surprise behind all this was that we had its regulation and composition—is turning out previously assumed that dendritic cells in vivo to be one of the hallmark differences between are fully ready to initiate immunity because of dendritic cells and macrophages. their high levels of MHC class II (MHCII) Niki Romani likewise made surprising find- molecules in spleen and in skin. But when Ira ings with dendritic cells from the skin. The Mellman and his colleagues at Yale decided immature cells capture antigens while the ma- to bring expertise in cell biology to dendritic ture ones are ineffective; in contrast, the mature cells, they found that the MHCII products are cells are very strong immune stimulators for T largely sequestered within the endocytic system cells specific for antigens captured earlier (43). (39). There, the MHCII molecules wait for a This finding was one of the early indications in www.annualreviews.org • Decisions on Dendritic Cells 7
  9. 9. IY30CH01-Steinman ARI 17 November 2011 12:14 immunology that the initiation of immunity re- and dendritic cells. In our cultures, the different quires two large components: (a) antigen cap- myeloid progeny were separated on the basis ture and presentation and (b) the expression of of plastic adherence and clustering properties, many accessory functions. I still prefer the term allowing us to show the typical morphology and “accessory” because it encompasses the many phenotypic features of dendritic cells, includ- specializations of dendritic cells for initiating ing the later finding that the immature forms immunity. These go beyond formal costimula- are capable of modest but clear phagocytic tion of the T cell receptor. activity (52). Soon thereafter, using monocytes Many investigators use the word maturation rather than marrow progenitors, Federica when only “phenotypic maturation” has been Sallusto and Antonio Lanzavecchia (53) and documented. Typically, this means increased Romani, Schuler, and colleagues (54) de- expression of CD40/80/86 and more recently termined that a combination of GM-CSF PD-L1/CD274 and PD-L2/CD273. Pheno- and IL-4 (or IL-13) can induce the initial typic maturation is not identical to functional differentiation of human monocytes to acquire maturation or immunogenicity. Many changes phenotypic features associated with dendriticAnnu. Rev. Immunol. 2012.30. Downloaded from www.annualreviews.orgby Universidade Federal do Amazonas on 03/21/12. For personal use only. that comprise the maturation phenotype are cells and that development is completed actually secondary to inflammatory cytokines, following application of a maturation stimulus which Shin-ichiro Fujii and Kanako Shimizu (55). Consistent with the idea that maturation found when they studied functional maturation is the essential link between innate and adaptive mediated by natural killer T (NKT) cells in vivo immunity, Sallusto and Lanzavecchia studied (44, 45). A big gap currently is the incomplete lipopolysaccharide (LPS) as a maturation molecular understanding of functional matura- stimulus (55), before the identification of tion, i.e., what events take place directly when responsible Toll-like receptors (TLRs). a dendritic cell encounters a microbial product, These methods to develop large numbers an alarmin, an innate NK cell, or a CD40 ligand of monocyte-derived dendritic cells in vitro on a mast cell and platelet. Cytokine production changed the field because investigators could by dendritic cells is a critical initial step in mat- more easily study their immunizing proper- uration, but many cells make cytokines. One ties. This included Inaba’s use of antigen- needs in the future to identify the constellation loaded dendritic cells to immunize healthy of changes in dendritic cells, not only cytokines, mice (52, 56) and later Madhav Dhodapkar’s that leads to the initiation of the appropriate and Nina Bhardwaj’s research showing that immune response, and sometimes to inappro- antigen-loaded dendritic cells could immunize priate ones. These include allergy as reviewed humans (57, 58). But still, something impor- by Bart Lambrecht and Hamida Hammad from tant was missing. Despite the use of GM-CSF Ghent (46) and systemic lupus erythematosus in these systems for dendritic cell development, as reviewed by Lars Ronnblom and Virginia Ken Shortman in Melbourne showed that mice Pascual from Uppsala and Dallas (47). deficient in GM-CSF and GM-CSF receptor The other area of dendritic cell develop- can have quite normal numbers of dendritic ment that we decided to study in the early days cells in the steady state (59). of the field was the identification of progeni- Several investigators have uncovered the tors. With Gerold Schuler and Kayo Inaba, we missing link in vivo, another hematopoietin, began this demanding project in mice (48–50), flt-3L. Eugene Maraskovsky, with the former while Jacques Banchereau, Christophe Caux, Immunex Corporation in Seattle, found that and colleagues in Dardilly were doing similar repeated injection of flt-3L into mice (60) experiments with human CD34+ progenitors and humans (61) leads to a dramatic 10- to (51). The first concept was that dendritic cells 15-fold expansion of dendritic cells. The develop from a common myeloid progenitor laboratories of Li Wu in Melbourne (62) and that gives rise to granulocytes, macrophages, Markus Manz in Bellinzona (63) established 8 Steinman
  10. 10. IY30CH01-Steinman ARI 17 November 2011 12:14 that the dendritic cell progenitor in marrow is surprising because it had been overlooked responsive to flt-3L. Waskow and Liu, working for so long. The monocyte–to–dendritic cell in the Nussenzweig laboratory at Rockefeller, conversion occurs when mice are given a high defined the progenitors of dendritic cells in dose of LPS or gram-negative bacteria (69). the bone marrow (64–66). They discovered Rapidly, within 6 h, blood monocytes move intermediates in the myeloid differentiation into peripheral lymph nodes and differentiate pathway that define the split between dendritic via TLR4, Trif, and CD14 into typical func- cells and monocytes during development. In tional dendritic cells. Importantly, the addition addition, they showed that under steady-state of LPS to mouse or human monocytes does conditions, dendritic cell–committed precur- not directly convert monocytes to dendritic sors emigrate from the bone marrow and seed cells; rather, additional, still unknown events lymphoid and nonlymphoid tissues, where must occur in mice that allow this transition they divide under the control of flt-3L to fill to take place. Also uncertain are the functions the dendritic cell compartment. Thus, in the of monocyte-derived, flt-3L-independent steady state, a critical part of the definition cells in many tissues, particularly lung andAnnu. Rev. Immunol. 2012.30. Downloaded from www.annualreviews.orgby Universidade Federal do Amazonas on 03/21/12. For personal use only. of the dendritic cell lineage is its dependence intestinal lamina propria. These are often on flt-3L. An exception is the epidermal called dendritic cells, but more study of their Langerhans cell, which as reviewed by Miriam antigen-presenting functions is required, Merad and colleagues has a separate origin (67). as Saurabh Mehandru is now undertaking. Frederic Geissmann, now in London, Curiously, the first nonlymphoid tissue in defined a common bone marrow progenitor which functional flt-3L-dependent and M- that gives rise to both monocytes and dendritic CSF-dependent dendritic cells have been stud- cells. The split between the two pathways ied side by side is probably the most demanding was defined by Liu and Nussenzweig (64): one, the mouse aorta, as shown recently by Monocytes remain dependent upon M-CSF, Jaehoon Choi and Cheolho Cheong (70). and the dendritic cells remain dependent on Monocyte-derived dendritic cells in vivo flt-3L. The dendritic cell progenitor moves share a property with their cultured counter- into lymphoid and nonlymphoid organs (64), parts, which is the capacity to present nonrepli- the latest example being Kang Liu’s research cating proteins on MHC class I (69). This is with the meninges of the brain (68). Niroshana termed “cross-presentation” and is a hallmark Anandasabapathy is leading a new clinical of one subset of dendritic cells in lymphoid tis- study with Celldex Therapeutics to pursue sues, the CD8+ subset. This allows monocyte- flt-3L in people. We want to confirm that derived dendritic cells to cross-present antigens this hematopoietin can expand many different to CD8+ T cells from immune complexes, as types of dendritic cells roughly 10-fold in shown by Sebastian Amigorena in Paris (71), people. After following U.S. Food and Drug and from dying infected cells, as shown by Administration guidelines to reevaluate in Matthew Albert and Nina Bhardwaj in New detail new lots of flt-3L clinical product for York (72). safety and efficacy, the product can then be The advances in knowledge of dendritic used, for example, to test whether dendritic cell development that are coming from many cell expansion can enhance immune control in laboratories now make it possible to better vaccination and in autoimmunity. understand and work with the lineage. The But there may be a way for monocytes future will yield even more clarity when to become dendritic cells in vivo in parallel the driving forces for the gene-expression with the much-used human monocyte tissue programs of dendritic cells are unraveled at the culture system also mentioned above. Cheolho levels of transcription factors and microRNAs. Cheong, Ines Matos, and Chae Gyu Park found Several relevant transcription factors have been a surprising pathway for this differentiation, identified for dendritic cell development, e.g., www.annualreviews.org • Decisions on Dendritic Cells 9