1 histórico das células dendríticas - primeira apresentação.pdf

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. Steinman
January 14, 1943 – September 30, 2011

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. Steinman

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


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 are

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


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 equally

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


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 these

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


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, we

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).



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,

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


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 Immunopathology

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



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 dendritic

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


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 and

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.,


1 histórico das células dendríticas - primeira apresentação.pdf

1 histórico das células dendríticas - primeira apresentação.pdf

Recommended

Recommended

More Related Content

More from ufamimunologia

More from ufamimunologia (13)

Recently uploaded

Recently uploaded (20)

1 histórico das células dendríticas - primeira apresentação.pdf