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THE DENDRITIC CELL SYSTEM
AND ITS ROLE IN
1IMMUNOGENICITY
Ralph M. Steinman
Laboratory of Cellular Physiology and Immunologyand
Irvington Institute, The Rockefeller University, NewYork,
New York 10021
KEYWORDS:primary immuneresponse, antigen presenting cells, Langerhans
cells, homing,antigen processing
Abstract
Dendritic cells are a system of antigen presenting cells that function to
initiate several immuneresponses such as the sensitization of MHC-restricted T cells, the rejection of organ transplants, and the formation of Tdependent antibodies. Dendritic cells are found in many nonlymphoid
tissues but can migrate via the afferent lymphor the blood stream to the
T-dependent areas of lymphoid organs. In skin, the immunostimulatory
function of dendritic cells is enhanced by cytokines, especially GM-CSF.
After foreign proteins are administered in situ, dendritic cells are a principal reservoir of immunogen.
In vitro studies indicate that dendritic cells
only process proteins for a short period of time, whenthe rate of synthesis
of MHC
products and content of acidic endocytic vesicles are high. Antigen
processing is selectively dampenedafter a day in culture, but the capacity
to stimulate responses to surface bound peptides and mitogens remains
strong. Dendritic cells are motile, and efficiently cluster and activate T
cells that are specific for stimuli on the cell surface. Highlevels of MHC
class-I and -II products and several adhesins, such as ICAM-1and LFA3, likely contribute to these functions. Therefore dendritic cells are specialized to mediate several physiologic components of immunogenicity
~ Abbreviations: APC,antigen-presenting cell; LC, Langerhans cells;
cyte reaction; MHC,major histocompatibility complex.
MLR,mixed leuko-
271
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272 STEINMAN
such as the acquisition of antigens in tissues, the migrationto lymphoid
organs, and the identification and activation of antigen-specific T cells.
The function of these presenting cells in immunologic
tolerance is just
beginningto be studied.
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INTRODUCTION
Manytissues contain a trace populationof cells with an unusualdendritic
shape, high levels of MHC
class-II products, and strong accessoryfunction
for the stimulation of T lymphocytes.Aclearer picture of the physiology
of these cells is emergingandis reviewedhere. Dendritic cells comprisea
system that occupies discrete portions of nonlymphoidand .lymphoid
organs and is interconnected by defined pathwaysof movement
(Table 1).
In each site, dendritic cells share features of structure and function, the
mostnotable being the ability to capture antigens and initiate T celtmediatedimmunity.Themechanisms
of dendritic cell action are important
for understanding how T cells are primed and howone might begin
to manipulate the immuneresponse at the early sensitization phase of
immunity.Three areas of function are considered here, each exhibiting
differences fromother antigen-presentingcells (APC):a sentinel role
whichantigens are captured and presented, a migratoryfunction in which
dendritic cells moveto the T-dependentareas of lymphoidorgans and
bind antigen-specific T cells, and an adjuvantor activation role in which
T-cell growthand effector function are induced. Recent progress on dendritic cells is reviewedhere. Moredetailed reports on manytopics are in
Researchin Immunology
Volume140, International Reviewsin Immunology
Volume6, Advancesin ImmunologyVolume47, and EpidermalLangerhans
Cells, ed. G. Schuler.
DENDRITIC
CELLS:
A WIDELY DISTRIBUTED
AND CONNECTED SYSTEM OF POTENT ANTIGENPRESENTING
CELLS
Thecharacterizationof dendriticcells has requiredthe isolation of enriched
populationsof whatis a trace cell type in all tissues. Mouse
spleen remains
Table 1 The dendritic cell system--distribution
Nonlymphoid organs
Circulation
Lymphoid organs
and nomenclature
Langerhanscells, interstitial dendritic cells
Afferent lymphveiled cells, blood dendritic cells
Lymphoid
dendritic cells, interdigitating cells
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DENDRITIC
CELLS
273
the organ most readily analyzed, but manyother tissues have been utilized
successfully. Typically, dendritic cells do not adhere to tissue culture surfaces, especially after a day in culture, and they have low levels of Fc
receptors (FcR) but high levels of MHCclass-II products. Macrophages
in contrast are adherent, with abundant FcR but variable levels of class
II. Wereview the isolation and function of dendritic cells in different
sites and include newevidence that these antigen-presenting cells capture
antigens in situ and movefrom nonlymphoid to lymphoid organs.
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Nonlymphoid
organs
EPIDERMIS
Epidermal Langerhans cells are the best characterized nonlymphoiddendritic cells. It is feasible to prepare partially enriched (3060%)populations in mice, since keratinocytes can be depleted with ~-thy1 and complement plus adherence (1, 2). Partially enriched Langerhans
ceils suffice in most studies of function and are a better starting material
for purification by sorting and panning methods than are unfractionated
cells (2, 3). For humanepidermis there is no mAblike c~-thy-1 which binds
keratinocytes, but anti-CD 1 mAbselectively identify Langerhanscells (4).
Mouseepidermal Langerhans cells, in spite of high levels of MHC
classII products and detectable FoR are not active antigen-presenting cells
for the mixed lymphocyte reaction (MLR)or ~-CD3response. Activity
develops after a 1-3 day period of culture in which the cytokine GM-CSF
plays a key role (2, 3, 5). GM-CSFdoes not act simply to maintain
Langerhans cell viability, since another cytokine, TNF-cachectin, maintains viability without inducing accessory function (6). Structure and
phenotype also change in culture. The Langerhans cells enlarge, express
more MHC
class-II and adhesion molecules (below), and lose Fc receptors
and Birbeck granules. Romani et al (7) and Teunissen et al (8) noted
entirely analogous changes during the culture of humanLangerhans cells.
As a result, cultured Langerhans cells fully resemble blood and lymphoid
dendritic cells (1, 7, 9, 10).
There is evidence that Langerhans cells can leave the skin and move
via the afferent lymph to draining lymphoid organs. Cells with Birbeck
granules have been noted in lymph (11, 12) and lymph node (13).
contact allergens are applied, allergen is found 8-24 hr later on lymphoid
dendritic cells (14). Larsen (15) directly monitored the movementof
gerhans cells out of the epidermis. Grafting itself leads to movementin
either syngeneic or allogeneic hosts. Within a day, the Langerhans cells
enlarge and express high levels of MHCclass II. Epidermal Langerhans
cells numbers fall to about one third steady state, and the antigen-presenting cells appear in the dermis in what appear to be lymphatics. Similar
events occur in organ cultures of skin fragments. Langerhans cells move
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STE1NMAN
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into the dermis and then the culture medium(15). Kaplan et al suggest
that dermal Langerhans cells also arise from the blood in delayed type
hypersensitivity reactions (16).
HEARa"Fabre, Hart, and McKenzieshowed that the interstitium of most
organs, except brain, contain irregularly shaped cells that stain strongly
with mAbto MHCclass-II products and the CD45leukocyte antigen (17÷ leukocytes have been identified (20)
19). Twokinds of resident CD45
with a new antimacrophage mAb: macrophages that react with the mAb
and are radioresistant, and dendritic cells that do not react with the mAb
but are strongly MHC
class II-positive and are radiosensitive.
Larsen et al, studying mousecardiac allografts, found that the number
of interstitial Ia÷ dendritic cells fell during the first four days after grafting
(21). Using mAbspecific to polymorphisms of the heart donor, they saw
donor-derived, MHC
class II-rich dendritic cells in the spleen, indicating
migration from the heart via the blood stream. These results were confirmed in a rat limb transplant model(22).
L~WrtExcept for an initial report (23), there has been little study
isolated dendritic cells. In situ these antigen-presenting cells are in the
portal triads, in contrast to sinus-lining phagocytes(Kupffer cells) (18, 20).
LtrNGIn rat (24, 25), mouse(26, 27), and human(28, 29), dendritic
are selected on the basis of their low buoyant density, and lack of plastic
adherence and FcR. The enriched ceils have abundant MHCclass-II and
induce strong T cell-mediated immuneresponses. The parenchymais the
source of lung dendritic cells rather than the bronchoalveolar lavage fluid,
a standard source of macrophages.Holt et al (30) localized ÷ dendritic
cells to alveolar septae, as well as within and just beneath airway
epithelium. In tangential sections, the networkof epithelial dendritic cells
is reminiscent of epidermal Langerhans cells. Macrophagesare juxtaposed
to dendritic cells along the airway.
After aerosolization of proteins, lung dendritic cells present antigen,
since the isolated antigen-presenting cells directly stimulate antigen-specific
T-cell lines (24). To detect antigen-presenting cells function, suppressive
macrophages must be removed.
6tJa" Pavli et al succeeded in isolating dendritic cells from the lamina
propria of mouse intestine (31). Again, depletion of suppressive macrophages helped uncover the presence and function of dendritic cells.
The Circulation
~ LVraPr~ Afferent but not efferent lymph contains leukocytes
AFF~R~Na
termed "veiled" cells in rabbit (32), pig (33), rat (34, 35), mouse
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DENDRITIC
CELLS
275
human(37), and sheep (38). Like dendritic cells, veiled cells have a
buoyant density, low FcR and phagocytic activity, and high levels of MHC
class-II and antigen-presenting cell activity. The origin of veiled cells is
unclear. They may come from the interstitium and epithelium of many
organs, or from a pool of cells that leaves the blood, moves through
nonlymphoidtissues, and enters the lymph.
If protein antigens are administered intradermally, afferent lymphdendritic cells carry the antigen in a form that will trigger antigen-specific Tcell lines (38). Therefore, dendritic cells in lymphcan carry antigens
lymphoid tissues, as has been proposed for epidermal Langerhans cells.
BLOOD
In human blood, < 0.1% of the white cells are dendritic cells.
Prior enrichment methods fell short of substantial purity, but >90%
purity has nowbeen achieved (39). Enrichmententails successive depletion
of T cells (sheep red cell rosetting), monocytes(adherenceto plastic or
coated plates), and B plus NKcells (pelleting in metrizamide). Together,
and whenperformed in the above sequence, these steps yield an E rosette
negative, nonadherent, low-density fraction with 30--60%dendritic cells.
Further purity is obtained by panning or sorting with mAb, especially
to CD45RA,that selectively react with the contaminants. Although this
isolation approach is labor-intensive, one simultaneously secures populations of other cell types, each depleted of dendritic cells (39).
The purity of the populations can be assessed by three approaches with
comparable results. One approach uses mAband flow cytometry (39)
phenotype the cell fractions. Markersthat dendritic cells lack are CD3(T
cells), CD14(monocytes), CD19/20 (B cells), and CD56/57 (NKcells).
Abundantproteins are classoI and -II MHC
products plus a distinct array
of receptors and adhesion molecules (see below). The second approach
to observe cell fractions live by video microscopy (39). Dendritic cells
continually extend and retract large lamellipodia or "veils." Noother cell
in blood showsthis motility. The third approach is to test MLRstimulatory
function. The dendritic cells are potent, e.g. in cultures of 105 T cells,
1-3 × 10 3 allogeneic dendritic cells induce an MLRcomparable to that
induced by the standard population of 105 bulk mononuclears. Monocytes
and B cells have little or no stimulating activity (21).
Dendritic cells in blood may be migrating from nonlymphoidtissues to
spleen. Evidence for the latter was recently obtained in a rodent heart
transplant model(39). Alternatively, dendritic cells maybe en route from
the marrowto nonlymphoid tissues.
Lymphoid
Organs
TONSILSubstantial purification of humantonsil dendritic cells also has
been obtained (40). The cells are strong MLR
stimulators, and their distinct
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276
STEINMAN
surface composition has been outlined with a panel of mAband immunoperoxidase labeling. The results are included in the next section.
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T-DEPENDENT REGIONS OF PERIPHERAL LYMPHOID ORGANS In
sections of
the T-dependent regions of lymphoid organs, there are "interdigitating
cells" (41) which resemble dendritic cells in cytology and phenotype (42,
43). If dendritic cells from mousespleen (44) are administered into
blood or foot pads, Austyn et al noted homing to the T-dependent areas.
Fossuminjected radiolabeled afferent lymphdendritic cells into rats. By
light and electron microscopy, the injected cells assumedthe location of
interdigitating cells (45). Little is knownabout the efficiency of this homing.
Possibly the only cells that are retained are those that find T cells specific
to the presented antigens. The reason is that the flux of dendritic cells in
lymphcan be 105/hr, yet these antigen-presenting cells do not accumulate
in lymph node or efferent lymph. Given the substantial turnover of cells
in lymph and in spleen (35, 46), most dendritic cells may not live long
upon reaching the lymphoid organ.
In spleen, dendritic cells are more numerousthan the interdigitating
cells of the periarterial sheaths. Whendendritic cells are sorted from fresh
spleen suspensions (see below), only a subpopulation label clearly with
NLDC145
(47), a mAbto interdigitating cells in the central periarterial
sheaths (48). In section, nests of dendritic cells lie in the periphery of the
T area interrupting the marginal zone of macrophages (49, 50). Both
cells and antigens leave the arterial tree in the marginal zone, so in effect,
dendritic cells are positioned like "doors" through whichT cells pass upon
entry into the periarterial
sheaths. Lymphoidorgans may contain two
populations: peripheral [?migratory], short-lived dendritic cells, and
central, long-lived interdigitating cells.
DENDRITICCELLSFRESHLYISOLATEDFROMMOUSE
SPLEENAS evident
above, dendritic cell isolation requires manysteps that can take a day or
more. Since viability and function can be influenced by cytokines like GMCSF, IL-1, and TNF(2, 3, 6, 51, 52), it is important to characterize fresh
isolates. This recently was done in mouse spleen using a new mAb,N418
to murine CD1lc (47, 49). Dendritic cells are the maincell expressing high
levels of CD1lc in the steady state in spleen. Fresh suspensions contain
about 1.5% N418+ cells, while peritoneal washings and blood have few.
Two-color immunolabelingshows that splenic N418+ cells have the phenotype of dendritic cells (47). Sorted N418+ cells assume a typical veiled
morphologyif cultured for a day.
Fresh, sorted N418+ dendritic cells actively stimulate the MLRand
present protein antigens to sensitized T cells (47). If proteins are given i.v.
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DENDRITIC CELLS
277
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or i.p., the N418+ fraction is the main source of immunogenwhen spleen
fractions are applied to antigen-specific T cells (53).
"r~¥~ctJs Large, bone marrow-derived, class II-rich dendritic cells are
found in the medulla (54, 55). Theselikely are the "interdigitating cells"
noted by electron microscopy (56) or the "dendritic cells" in enzymedigested thymus (57-59). Crowley et al succeeded in enriching mouse
thymic dendritic cells to a high degree of purity, using the same approach
as was used in spleen (10). Adherent cells with a low buoyant density were
cultured overnight so that most dendritic cells dislodged. The dendritic
cells were about twice the size as in spleen but similar in phenotype and
function. If mgdoses of proteins are given i.v., thymicdendritic cells pick
up antigen in a form stimulatory for T cells (58).
Summary."a Dendritic Cell Lineage
Nonlymphoidorgans, blood, afferent lymph, and lymphoid tissues (see
Table 1) contain dendritic cells with different namesbut similar properties.
To enrich them, one selects for low buoyant density, nonadherence to
plastic especially after a day in culture, and absence of certain markers
found on other cell types. These approaches simply deplete other cells but
do not positively select for cells that are distinct in shape and have abundant MHC
class II plus strong antigen-presenting cell function. This indicates that the negatively selected dendritic cells are an independent cell
type.
Evidenceis growingthat dendritic cells in different tissues, as defined
morphologically and by a distinct group of cell surface markers, are part
of a system connected by movementand homing. Dendritic ceils in nonlymphoidorgans, such as epidermal Langerhanscells and heart interstitial
cells, can give rise to "veiled cells" in the afferent lymphand blood which
migrate to lymphoid tissues where they are isolated as "dendritic" or
"interdigitating" cells. Coupled with these migratory abilities is the
capacity to capture antigens in an immunogenicform in situ.
It seemsappropriate to classify the cells in Table I as a separate lineage
given their distinct features and tissue distribution. There is no evidence
that other white cells convert into dendritic cells or vice versa, even if
challenged with a variety of cytokines. For example, macrophage and
granulocyte factors, M-CSFand G-CSF, have no known effects on dendritic cells, in contrast to their profound effects on typical phagocytes.
Nonetheless, the progenitor for the putative dendritic cell lineage has
not been isolated. Dendritic cells in spleen and lymph originate from a
proliferating pool of precursors and undergo rapid turnover (35, 46, 60),
but the site for proliferation (3H-thymidine uptake) is not known.A bone
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278 STEINMAN
marrowprecursor exists (35, 46, 54, 61), but conditions have not been
identified that direct its growthin culture.
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THE DENDRITIC
SPECIALIZATIONS
CELL SURFACE:
FOR ANTIGEN
PRESENTATION
In mouseand human,the fluorescence activated cell sorter (FACS)now
has provideddetailed descriptionsof the dendritic cell surface(10, 39, 47).
The results are diagrammed(Figure 1). The surface is distinct among
leukocytesin manyrespects andis consistent with their functional capacities (see below), including antigen presentation (abundantsurface
products), active clustering with T cells (high levels of several adhesins),
and weakphagocytosis (low amountsof Fc and complementreceptors).
Mostantigens are expressed in a homogeneous
fashion on dendritic cells
fromdifferent sites, but deviationscan occur. Thesemayrepresent differences expressed as dendritic cells mature and migrate from peripheral
tissues to the T areas.
Products of the MHC
Consistent with their strong antigen-presentingcell function, dendritic
cells express all class-ll MHC
genes at high levels. Both I-A and I-E
MHC
Class i q’-t- +++
Class II
CD19-- 29-- 21 --22--40 +Ig -Tcell
NK cell
CD56--57--
CD16--32 + or-- 64 --23 +
1[
~1~
/~
~2Integrins
O~her receptors
~~
+CD35-M’CSFCD25
~"/~~.j
Leukocyte common antigen
"CD 45+45R~
Foure 1.
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DENDRITIC
CELLS
279
are abundant in the mouse, and HLA-DP,DQ, DR likewise in human.
Monocyteshave low levels of DPand DQ(39). Dendritic cells have surface
invariant chain (CD74), as evidence by FACS(39) and precipitation
~25I-labeled cells with polyclonal antibody (62).
Polymorphic class-I products also are abundant (39, 63-65) and can
used to monitor the repopulation of dendritic cells in bone marrowchimeras (66) or movementduring transplantation
(22). Nonpolymorphic
class I (such as Qa and TI), which maypresent antigens to the ~/6 subset
(68), have not been evaluated on dendritic cells. CD1, whichis not encoded
in the MHC
but is class I-like and mayact as a restriction element for y/6
T cells (69), is abundant on dendritic cells in skin (CDla) (4, 70)
afferent lymph (CDlb) (38).
Fc and C3 Receptors
(FcR,
C3R)
Dendritic cells are not actively phagocytic. Consistent with this, there is
little or no expression of FcyR (CD16, CD32, CD64) or C3R (CDllb,
CD21, CD35), as assessed by staining with mAbor binding of opsonized
particles. Yet some exceptions are apparent. In skin, CD32FcTRare noted
(1, 71, 72), but their levels fall by 90%when the Langerhans cells are
cultured (8, 73, 74). Only freshly isolated Langerhanscells actively process
andpresent native proteins (see below); this fact leads to the idea that
Fc~Ron fresh Langerhanscells are involved in antigen uptake (75). Sheep
lymph dendritic cells have cytophilic Ig and specific antibody enhances
antigen presentation (76).
Fc~Rhave been studied on epidermal Langerhans cells. Binding of IgE
is noted in situ in the skin of atopic patients (77), but the FceR-mediating
bind.ing has not been identified. Low-affinity FceRII (CD23)are upregulated with IL-4 and IFN-7 (78). Langerhans cells are implicated in the
transport of contact allergens as well (12, 79).
C3bi (CD1lb) receptors typically are present at trace levels with the
exception of mouseLangerhans cells where they are more readily detectable (1).
Other receptors used by phagocytes to scavenge particulates and microorganisms have not been studied. Dendritic cells lack mannose-fucose
receptors (35), but no studies have been published on other receptors, e.g.
for lipoproteins and scavenging. The lack of phagocytic receptors does not
meanthat particulate antigens are not processed. It is possible these antigen-presenting cells take up small numbersof particles at defined stages of
their natural history, or that particles are processedat the surface. Afferent
lymphdendritic cells do not internalize test particles, yet someof the cells
have what appear to be phagocytic inclusions (35). The latter perhaps were
acquired in the tissues prior to entry into the lymph.
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280 STEINMAN
Integrins
and Adhesins
These molecules contribute to cell binding and homing,whichare both
importantfeatures of dendritic cell function. Dendriticcells can havehigh
levels of p150/90or CD1 l c but lowCD~ 1 b (39, 49). CD11 a or LFA-1
found on dendritic cells in mousespleen and humanblood (39, 80) but
not skin (8, 73). Dendriticcells also havehigh levels of other adhesins,
ICAM-1
(CD54),LFA-3(CD58),and fl~ integrin (CD29)(7,
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Differentiation
Antigens
Manygroups are trying to prepare dendritic-cell specific mAb,but this
has proven problematic. This is not for a lack of immunogenicity,since
large numbersof mAbto shared markers are obtained following immunization with dendritic cells, e.g. mAbto MHC
products and integrins
(49). A groupof three mAbare useful in the mouse(50). 33D1reacts
mostdendritic cells in spleen and Peyer’s patch, but not skin and thymic
medulla(10). NLDC145
reacts with dendritic cells in skin and in the
dependentregions of several lymphoidorgans, but also binds to thymic
epithelium(48). N418anti-CD1lc reacts strongly with dendritic cells, but
CD1lc can be upregulated on macrophages.
Manymoleculesare expressedin a cell-type restricted fashion and are
useful for distinguishing dendritic cells. For example,dendritic cells in
humanblood (39) lack CD3(T cells), CD19-22(B cells), CD13-15
the c-fms receptor for M-CSF(phagocytes), and CD56/57(NKcells).
Dendritic cells can expressthe B cell-activation markerCD40(7, 39, 40),
and expression of CD4and CD8also occurs (10, 47). Someuseful markers
that mousedendritic cells lack are CD45RA,
thy-1, and certain phagocyte
markersthat lack a CDdesignation (SER-4,RB-6)(50).
PRIMARY RESPONSES
INDUCED BY DENDRITIC
CELLS: DISTINCT
ANTIGEN-PRESENTING
CELL
REQUIREMENTS
FOR THE AFFERENT
AND EFFERENT
LIMBS OF IMMUNITY
Theterm "antigen-presentingcell" does not fully describe the function of
dendritic cells. Theirdistinctive role is to initiate T-dependent
responses
from quiescent lymphocytes.Oncesensitized, the T lymphoblastsreadily
interact with other antigen-presentingcells. In effect, efficient T-cell
responses both in vitro (81-83) and in vivo (84) seem to occur in
phases. In the afferent limb, dendritic cells are specializedto identify and
activate trace clones of antigen-reactiveT cells whilein the efferent limb,
the sensitized blasts find other antigen-presentingcells to induceeffector
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DENDRITIC CELLS
281
functions such as macrophage
activation and IL-1 production, and B-cell
antibodyresponses.In this section, several primaryresponsesare reviewed,
while in the next, aspects of mechanism
are considered.
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The Primary Antibody Response
Theneed for spleen adherent cells in the primaryantibody response by B
and T lymphocytes
(85) led to the discoveryof dendritic cells whichproved
to be essential accessories (86). Whenforeign red blood cells are the
antigen, dendritic cells stimulatethe productionof helper factors bypassing
the needfor intact T cells (87). For haptencarrier conjugates,the needfor
dendriticcells is to sensitize carrier-specificT cells whichdirectly interact
with hapten-specificB cells as antigen-presentingcells (82). TheB cells
becomeresponsiveto antigen-nonspecificcytokines, and this all occursin
discrete aggregatesof dendritic, B, andT cells (88, 89).
Someuncertainty exists concerningthe relative roles of dendritic cells
and B cells as antigen-presentingcells for sensitizing helper cells in situ
(90). The lymphnodes of mice that are treated with anti-# from birth
cannot be primedwith proteins in adjuvant (91-94). The nodespresumably
are depleted of B cells and not dendritic cells. In contrast, in studies of
antigen-presentingcells functionfor antibodyresponses,there are in vitro
data that mousespleen responsesrequire dendritic cells (82, 88) and
vivo findingsthat B cells in chickensare not the initial antigen-presenting
cells for responsesto heterologousred cells (95). In a studywhereantigenpulsedantigen-presentingcells havebeenused to induceantibodyin situ,
it has beenfoundthat dendritic cells inducethe formationof antiviral and
antiidiotypic antibodies(96).
Primary Responses to Protein Antigens In Situ
If spleendendriticcells are exposedto proteinantigensin vitro andinjected
+ T cells in the draining lymphnode are
into the foot pads of mice, CD4
sensitized (97). Responsiveness
peaksat day 5, wanesby day 9-12, and
rapidly inducedby rechallengewith antigen-pulseddendritic cells. When
spleen cells, whichare 60%B lymphocytes,are pulsed with antigen and
then compared
to dendritic cells, the spleencells are muchless efficient as
antigen-presentingcells in vivo (97). × 106 spleen cells (t he ma
ximum
that can be given readily in one doseinto a foot pad) induceweakresponses
whereas2 × 105 dendritic cells are muchmoreactive. As such, spleen B
cells lack direct sensitizing function at least for bulk exogenous
proteins.
Peritoneal macrophages
are totally inactive as antigen-presentingcells in
this in vivo assaysystem.
Theinjected dendritic cells do not simplycarry antigens to be presented
by host antigen-presentingcells. This can be shownby injecting pulsed,
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282 Sa’Er~MAr~
parentalstrain dendriticcells into F 1 recipients. TheTcells that are primed
respondto antigen in the context of MHC
class-II productsof the injected
dendritic cells (97). This is the first instancein whichantigen-pulsedantigen-presentingcells haveprimedT cells in an MHC-restricted
fashion in
vivo.
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Viral Antigens
The standard assay for studying the generation of antiviral CTLis to
prime a mouseby exposure to virus and induce CTLby rechallenge in
vitro. Dendritic cells from mice that have been infected with Moloney
leukemiavirus are active antigen-presenting
cells for inducingvirus-specific
CTL(98). Dendriticcells also presentSendaito virus-primedspleen(98).
eachcase, dendritic cells are 30-100times moreactive than unfractionated
spleen.
Macatoniaet al found that dendritic cells serve as antigen-presenting
cells for primaryCTLresponses in the influenza system (99). A special
culture systemwasneeded.105 cells werecultured in 20 #1 drops that hung
fromwells of inverted Terasakiplates, a systemwhichmayimprovegaseous
exchange.Apuzzlingfeature is that high levels of CTLactivity developin
a primaryfive-day culture. This implies that the frequencyof precursors
for flu-specific CTLin naive mice is high. Hengelet al also noted that
dendritic cells inducethe formationof CTLto herpes simplexin a primary
system(100). Limiting dilution assays indicated that herpes-specific CTL
precursorsrepresent 1 in 400 of nylonwoolpassed, spleen T cells.
The Primary Mixed Leukocyte
Reaction
Thestrong stimulating activity of dendritic cells in the primarymixed
leukocytereaction (MLR)
is established (101). SmallB cells and monocytes
+ T cells (39) but do stimulate
trigger little or no responsefromresting CD4
activated T-cell blasts and T-cell clones (102, 103). Certain B blasts and
manyB-cell lines are in contrast capableof stimulatingthe mixedleukocyte
reaction(80).
Several lymphokinesform whendendritic cells stimulate the mixed
leukocyte reaction. IL-2 is noted on day 1 (81, 83, 104, 105) and other
factors soon thereafter: IL-4, IFN-y, and T cell replacing factors for
antibody responses (81, 104, 106). Detailed studies have not yet been
publishedthat comparedendritic cells with other antigen-presentingcells
for defined TH1and Tn2subsets.
+ T cells, but higher
Dendritic cells also stimulate an MLR
from CD8
antigen-presenting cell doses are needed(83, 105). Allospecific CTLare
detected at day4-5 usingdendritic to T-cell ratios of 1 : 10 or 1 : 30. The
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DENDRITIC CELLS
283
needfor relatively high dosesof dendritic cells couldmeanthat the antigen+
presenting cells are killed during the course of the response. TheCD8
mixedleukocytereaction is sizeable, with 30-40%of the culture at day 5
being T blasts that express CD25and MHC
class-II activation antigens.
+ cells but serve as targets in the
Monocytes
do not stimulate resting CD8
efferent limbof the response,i.e. for the CTLthat are inducedby dendritic
cells.
As few as 1 allogeneic dendritic cell per 100 CD4-responders also
induces strong NKactivity (K562targets) (105). Theprecursors to these
NKcells can be removedselectively prior to the MLR
by panning the
CD4-population with a-CD1lb mAb(105). That NKand allospecific
+ cells are inducedin the absenceof CD4
+ helpers indicates that ILCD8
2 and perhaps other cytokines can be generatedin substantial amountsin
the cultures.
COMPONENTSOF DENDRITIC CELL FUNCTION
--MECHANISMS OF IMMUNOGENICITY
Becausedendritic cells induceprimaryresponsesin vitro and in vivo, they
are important for studying immunogenicity
in a physiologic context. The
limitation is that only small numbersof dendritic cells are available from
any tissue, and no cell lines exist. Yet dendritic cell numbersare large
relative to their specializedtask, i.e. to identify andactivatethe verysmall
numbersof antigen-specific T cells that are present at the onset of an
immune
response.Todescribe these specializations, I do not use the "signal
1/signal 2" terminology,since the notion of two signals oversimplifiesthe
manyfeatures that contribute to dendritic cell function and does not
considerthe distinct physiologicproperties of different antigen-presenting
cells. Dendriticcell functioncan be consideredin three parts.
Sentinel Function--Processin#and Presentation of Antigen
SUMMARYOF RECENT ANTIGEN-PULSING EXPERIMENTS If
pulsed with rela-
tively low doses of soluble protein (100 #g/ml), dendritic cells stimulate
antigen-specific, primedT cells (62, 97). Chloroquineblocks pulsing (62)
as it doesin other types of antigen-presentingcells (107, 108), implying
needfor an acidic intracellular compartment.
Severalfeatures of antigenpulseddendritic cells are apparent:
1. Thenumberof pulsed dendritic cells neededto stimulate T cells is
low, about 30-100timesless than for mousespleen (62, 75, 97), a standard
antigen-presenting cell population whichcontains about 1%dendritic
cells.
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284
STEINMAN
2. Antigen-pulsed dendritic cells, cultured for 1-2 days without further
exposureto antigen, retain activity (62, 97). This could meanthat the levels
of MHC-peptidecomplexes are high, the turnover of complexes is slow,
or that fewer complexesare needed for presentation by dendritic cells. In
contrast, if macrophagesare pulsed, the turnover is rapid; the t~/2 of
presenting activity is a few hours (109).
3. Antigen-pulseddendritic cells, but not other antigen-presenting cells,
can be administered in situ to prime T cells without additional adjuvants
(97). Primingis restricted to the draining lymphoidtissue and is direct.
F 1 T cells are primedwith parental dendritic cells, sensitization is restricted
to the MHC
of the parental antigen-presenting cells.
4. The processing activity of dendritic cells is regulated. Only fresh
isolates from epidermis (62, 75) and spleen (97) present native proteins.
After a day in culture, the dendritic cells handle proteins poorly but are
the most potent antigen-presenting cells for stimuli that do not require
processing, e.g. peptides, alloMHC,and mitogens.
5. It is not yet possible to detect regurgitation of peptides processed by
other antigen-presenting cells onto dendritic cells. Such experiments are
possible with cultured dendritic cells which can present pcptides but not
proteins. If MHC-mismatched
spleen or peritoneal macrophages (97)
Ia- epidermalcells (62) are mixedwith protein plus cultured dendritic cells,
antigen-presenting cell function does not occur. If other cells regurgitate
immunogenicpeptides, one would expect the dendritic cells to have stimulated the T cells.
MECHANISMS OF ANTIGEN PROCESSING
IN DENDRITIC
CELLS
Several
vari-
are being analyzed to explain the differences between fresh and
cultured dendritic cells (see above). Both have high levels of surface MHC
class-II products, with cultured Langerhanscells expressing at least five
times more class II than fresh Langerhans cells (9, 110). Whenrhodamineovalbumin is used to monitor endocytosis, fresh and cultured Langerhans
cells internalize protein into intracellular granules (62). However,it is not
yet possible to rigorously quantitate endocytic activity in fresh and cultured
Langerhanscells, since these antigen-presenting cells are so weak. Stossel
et al recently madethe fascinating observation that freshly isolated Langerhans cells have more numerousacidic vacuoles, presumably endosomes,
whereas cultured mouse and humanepidermal Langerhans cells have some
acidic lysosomesbut few acidic endocytic vesicles (111).
Pure’ et al have identified two more striking differences between fresh
and cultured Langerhans cells (62). Fresh Langerhans cells actively synthesize class-II products, while cultured Langerhanscells synthesize other
proteins but not class II. By blocking synthesis with cycloheximide, the
ables
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DENDRITIC CELLS
285
efficiency with whichLangerhanscells can be pulsed with protein antigen
is reduced. In addition, fresh but not cultured Langerhanscells express
high levels of cytoplasmicinvariant chain. Thelatter enhancespresentation
by cell lines transfected with MHC
class-II genes(112). Thedata suggest
that the efficient processingof native proteins by fresh Langerhans
cells is
linked to the synthesis of MHC
class-II products. Perhaps newlysynthesized molecules,associated with invariant chains, are shuttled to an
acidic compartment
wherethere is ready access to peptide antigens.
Theability to downregulatethe presentation pathway,including a downregulation of class-II biosynthesis and a loss of invariant chains, is of
uncertain consequenceat this time. Antigen-pulseddendritic cells retain
antigen for long periods in an immunogenic
form (see above). Perhaps
acquiredpeptides wouldbe displacedif antigen processingwereto continue
in an unregulatedfashion. Continuedantigen processing, whendendritic
cells are migrating from nonlymphoid
tissues to lymphoidT areas, also
wouldallow self-peptides to predominateover exogenousones, and might
lead to autoimmunity
(see Discussion).
Although
dendritic cells can capture protein antigens, it is striking that
the absolute amountof protein that accumulatesintracellularly is small
(97). This suggests that while endocytic activity generates MHC-peptide
complexes,the relevant levels of processing and presentation are small
especially whencomparedto the size and activity of the vacuolar system
that is used to scavengeand degrade antigens in macrophages.Onemust
distinguish betweenendocytosisthat is primarily directed towardantigen
scavenging, the hallmark of the macrophage,and the muchlower amounts
that are associated with antigen-presentingcells function in dendritic and
B cells. It has beenknownfor sometime that macrophages
internalize and
completelydegradeat least 10,000protein moleculesper hour at the doses
of protein that are used traditionally to pulse antigen-presentingcells.
This scavengingfunction makesendocytosis, but not necessarily antigen
processing,easy to visualize in macrophages
(113).
CAPTURE
OFANTIGENS
IN SITUWhenantigens are administered in situ,
the dendritic cells can be isolated andshownto be carrying the antigen in
an immunogenic
form. This is tested by adding in vivo pulsed dendritic
cells to specific T cells. T-cell stimulationoccurswith lungdendritic cells
after aerosol administration of proteins (24), with afferent lymphsheep
dendritic cells after intradermaladministrationof protein (38), with draining lymphnodedendritic cells after applicationof a contact allergen (14),
and with thymicdendritic cells after an i.v. bolusof protein (58). If mice
are givenforeignproteinsi.v. or i.p., dendriticcells seemto be the principal
source of immunogen
relative to other cell types (53). Thelatter experi-
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286
STEINMAN
merits used selective depletion of in vivo pulsed antigen-presenting cells
with 33D1anti-dendritic cell mAband complement, as well as positive
selection with N418 anti-CD1 lc mAband the FACS(47).
The high
levels ofclass-I and -II MHC
molecules on dendritic cells could function to
carry manydifferent epitopes, as in the presentation of complexinfectious
agents or foreign cells, and/or to accumulate large numbersof individual
kinds of MHC-peptidecomplexes to better identify and stimulate resting
T cells. It is not yet possible to enumeratespecific MHC-peptide
complexes
on dendritic cells. However,Romaniet al (73) studied the numberofT cells
that bind and respond to presentation of anti-CD3 on defined numbers of
Langerhans cells. As few as 250 FcR per Langerhans cell are needed to
drive a T cell into cell cycle, and each Langerhanscell on average handles
10-20 T cells.
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THE LEVELS OF ANTIGEN/MHC ON THE DENDRITIC CELL SURFACE
Migratory
T Cells
Functions--
the Binding of Antigen-Specific
detailed above, dendritic cells can
migrate via blood or afferent lymph to the T areas of spleen and lymph
node respectively. This places the antigen-charged dendritic cell in the path
of recirculating T cells, enhancing the chance that relevant T-cell clones
can be selected.
The factors that stimulate and direct the movementof dendritic cells in
vivo are not clear. Simplygrafting skin to isogeneic hosts or placing skin
in organ culture induces egress of at least two thirds of the epidermal
Langerhanscells (l 5). This suggests that movement
is T cell independent.
However,homingmaybe T dependent since dendritic cells are not retained
in the spleens of nude mice (44). Dendritic cells express molecules that are
implicated in leukocyte homing, e.g. f12 integrins and CD44.
The migratory properties of dendritic cells do not preclude a role in
stimulating immunity locally. This may occur in secondary responses,
where dendritic cells are found in association with T cells at delayed type
hypersensitivity sites (16). However,in certain primary responses, like
sensitization to skin transplants (114) and contact allergens (115), afferent
lymphatics need to be intact--a point consistent with the idea that a flux
of dendritic cells is critical to immunogenicity.
MIGRATIONTO T-DEPENDENTAREAS AS
A feature that helps explain
dendritic cell function is the capacity to form stable clusters with antigenspecific T cells during primary responses. Other antigen-presenting cells
do not aggregate resting T cells but do bind sensitized T blasts (81, 82,
103, 116).
CLUSTERING OF ANTIGEN-SPECIFIC T CELLS
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DENDRITIC
CELLS
287
In the living state, thin sheets or lamellipodia extend from the dendritic
cell body in manydirections (33, 39, 117). The processes extend, retract,
and bend as if the antigen-presenting cells are probing the environment
around them. This motility, which is distinct amongwhite cells, likely
enables the dendritic cell to survey T cells and select antigen-specific ones.
Twoexamples indicate that the initial T-cell sampling occurs by an
antigen-independent mechanism.First, dendritic cells bind to T blasts that
are directed to specificities different from that present on the antigenpresenting cells (116). Second, whencultured in close proximity, dendritic
cells bind resting T cells in large numbers,too manyfor all to be antigenspecific (118). In both instances, boundT cells do not produce IL-2 unless
another stimulus like a mitogen is added. Antigen-independent binding
could provide a temporary state of antigen-presenting cell T-cell contact,
which may be essential for the appropriate TCR-antigen-MHC
interaction
to occur.
The molecules that mediate antigen-independent clustering have yet to
be identified. As mentioned, adhesins like ICAM-1and LFA-3are abundant on dendritic cells (39, 119). To date, mAbto//2 integrins have not
blocked heterotypic clustering with T cells in the mixedleukocyte reaction
(49, 80, 120), although ~-CD18mAbdoes block when the stimulus
sodium periodate (121). Other adhesins are under study, including CD2
and CD28.
Adjuvant Function--
T-Cell
Activation
IL-I ANDDENDRITIC
CELLFUNCTION
For years the main hypothesis for the
mechanism of T-cell activation has been that macrophage-derivcd IL-1
induces IL-2 release or responsiveness. Dendritic cells and B cells are active
antigen-presenting cells but are not knownto makeIL-1 (122-125), except
for a report of IL-1 in freshly isolated epidermal Langerhanscells (126).
It remains to be shown that a response of primary T cells, rather than
chronically stimulated cell lines, can be blocked with antibodies to IL-1 or
IL-1 receptors. For example, T lymphoblasts can engage macrophages
and induce IL-1 production (102, 103), but the T-cell proliferation that
occurs in these cultures is insensitive to neutralizing anti-IL-1 (103).
Attempts have been madeto identify other activating factors that might
be produced under dendritic cell control. These have yet to be found.
Inaba et al placed dendritic-T-cell clusters on one side of a millipore filter,
and T cells exposed to u-CD3on the other side. IL-2 was produced by the
clusters and crossed the filter, but no activation occurred even though the
TCRcomplex was occupied by ~-CD3(118). This suggests that the signals
provided by dendritic cells for T-cell activation are either active over short
distances or remain membranebound.
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288 STEINMAN
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CYTOKINES AMPLIFY THE FUNCTION OF DENDRITIC CELLS
While cytokine
production by dendritic cells is not yet well documented, cytokines can
enhance T cell-mediated immunityby amplifying the viability and function
of these antigen-presenting cells. Interestingly, each active cytokine has
distinct effects. Cachectin-TNFmaintains Langerhans cell viability but
does not enhance sensitizing function (6). IL-l enhances the function
skin, spleen, and thymicdendritic cells but does not increase viability (3,
51,127). GM-CSF
enhances both viability and function (2, 3, 52, 128).
As yet no cytokine has been identified that upregulates the level of
dendritic cell MHCproducts. Lymphokineslike IFN-~ and IL-4 induce
class-II products on macrophages and B cells, respectively, but do not
similarly increase expression on dendritic cells.
Specific cytokine receptors have not been identified on dendritic cells
except for the low affinity, p55, IL-2 receptor chain (CD25),first detected
on mouseepidermal Langerhans cells (129). CD25has since been found
dendritic cells from manysites--mouse spleen (10), rat afferent lymph
(52), humanblood (39)--but the function on these antigen-presenting cells
is not known.
By influencing dendritic cell function, cytokines mayplay a pivotal role
in immunogenicity, e.g. in skin, GM-CSF
release by keratinocytes (2) may
mobilize stimulatory dendritic cells. The phenotype of dendritic cells in
blood, lymph, and lymphoidorgans is that of a cell that has been activated
by cytokines, since leukocytes commonly upregulate MHCproducts,
adhesins, and IL-2 receptors upon activation. All of these molecules are
expressed at high levcls on dendritic cells (see above).
TO DENDRITIC CELL FUNCTION Many
ligand receptor systems, such as LFA-1/ICAMand LFA-3/CD2may contribute both to cell-cell adhesion and to signalling (130). Studies are underwayto test the effects ofmAbto these molecules on dendritic cell function,
particularly in clusters of antigen-presenting cells and T cells that are the
microenvironment for manyresponses in vitro. Because of the difficulty
encountered in identifying secreted lymphocyteactivating factors (above),
it is important to search for specific dendritic cell surface molecules that
contribute to T-cell signalling. However,it is possible that dendritic cells
use surface signalling molecules that can be expressed by manycell types,
such as LFA-3 and ICAM-1,but that the key feature of these antigenpresenting cells is the capacity to upregulate manyadhesion/signalling
systems in a T-independentfashion at the site of antigen deposition. Recent
studies of humanLangerhans cells indicate that dendritic cells rapidly
upregulate adhesion molecules in vitro, in the apparent absence of T cells
(7, 8). Thesematuration events, coupled with the other specializations (see
SURFACE MOLECULES CONTRIBUTING
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DENDRITIC
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above) in antigen handling and migration,
genicity of antigen-pulsed dendritic cells.
CELLS
289
help explain the immuno-
CLONAL
EXPANSION
OF T CELLSFor many mitogens, such as lectins and
anti-CD3 mAb, the accessory function of macrophages compares with
that of dendritic cells. Mitogens maymediate macrophage-Tcell clustering, which is not observed in primary antigen-specific responses. However,
the T-cell function being measured is the onset of DNAsynthesis, not
long-term clonal expansion. Whenantigen-presenting cell requirements
for the latter were addressed (131), dendritic cells proved to be remarkably
more efficient than other antigen-presenting cells. A thousand dendritic
cells mediate the optimal cloning efficiency of single T cells in the presence
of lectin and exogenousIL-2. Someclones develop with just one dendritic
cell, while few clones develop with up to 104 monocytes.In effect, dendritic
cells are able to induce long-term T-cell responsiveness to growth factors
like IL-2.
Using dendritic cells as immunoadsorbents,Pancholi et al cloned T cells
that had been bound in clusters (132). Macrophages had to be removed
to enhance cluster formation. Antigen was needed to select but not expand
the clones. These findings, plus those showing antigen capture in vivo,
suggest a use for dendritic cells to select clones that are specific for physiologically relevant antigens on antigen-presenting cells in vivo.
DISCUSSION
This review has emphasized dendritic cells and immunogenicity. These
antigen-presenting cells are in essence nature’s adjuvant and allow one to
study responses to specific antigens both in tissue culture and in whole
animal models. The data discussed above on distinct antigen handling
functions, the lack of IL-1 production, the ability to migrate and form
stable contacts with T cells, the afferent and efferent limbs of antigenpresenting cells function, all have becomeapparent via direct analyses of
this trace but specialized subset of antigen-presenting cells.
Given their role in presentation of antigens on self and allogeneic MHC
molecules,it will be important to test the contribution of dendritic cells to
self-tolerance. Metzinger &Guerder found that dendritic cells tolerized
cells in organ cultures of fetal mousethymus (133). Inaba et al obtained
data in an Mls system that neonatal tolerance can be induced with dendritic
cells, but it is the result of clonal anergy not deletion (134). Fairchild
Austyn workedout methods for placing dendritic cells within the medulla
of thymic organ cultures (135); these methodsshould be useful for future
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290
STEINMAN
studies. The capacity of dendritic cells to induce suppressor cells against
self-reactivity has not beentested.
Given the likelihood that manyself-reactive T cells are not tolerized
(136), one must consider that the avoidance of self can also reflect the
extent to which a given protein is captured and presented by dendritic
cells, and the extent to which dendritic cells are activated and mobilized
by cytokines or other factors. In other words, tolerance in the adult
operates not only at the level of the T cell but also at the level of the
dendritic cell. For manyantigens, the distinction is not between foreign
and self, but in the extent to which a given protein, foreign or self, is
captured and presented by stimulatory dendritic cells.
ACKNOWLEDGMENTS
This work has been supported by grants AI13013, AI24540, and AI24775
from the National Institutes of Health.
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Annu. Rev. Immunol. 1991.9:271-296. Downloaded from arjournals.annualreviews.org
by Rockefeller University on 08/15/07. For personal use only.