Taking Dendritic Cells into Medicine

Ralph M. Steinman and Jacques Banchereau

The Rockefeller University, New York, NY 10021 and Baylor Institute for Immunology

Research, Dallas, TX 75204

Dendritic cells (DCs) orchestrate a repertoire of immune responses that bring about

resistance to infection and silencing or tolerance to self. In the settings of infection and

cancer, microbes and tumors can exploit DCs to evade immunity, but DCs also can

generate resistance, a capacity that is readily enhanced with DC targeted vaccines. During

allergy, autoimmunity and transplant rejection, DCs instigate unwanted responses that

cause disease, but again DCs can be harnessed to silence these conditions with novel

therapies. Here we present some medical implications of DC biology that account for

illness and provide opportunities for prevention and therapy.

Immunology is a major force in medicine. It is needed to understand how prevalent diseases

(Fig. 1) come about and how to develop preventions and treatments. This broad reach of the

immune system reflects its two functions: to recognize diverse substances termed antigens, and

to generate many qualitatively distinct responses. Dendritic cells (DCs), named for their probing,

tree-like or dendritic shapes (Gr. dendron, tree)1,2 (Fig. 1), are pivotal for both: recognition of a

universe of antigens and control of an array of responses.

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Previously, we reviewed some biological features of DCs3,4. Here we illustrate medical

implications of DCs, which control a spectrum of innate and adaptive responses. Innate

immunity encompasses many rapid reactions to infection and other challenges5-9. Adaptive

immunity, in contrast, is learned or acquired more slowly, in days to weeks; it has two hallmarks:

exquisite specificity for antigens, and a durable memory to develop improved function upon re-

exposure to antigen. Adaptive responses are either immunogenic, providing resistance in

infection and cancer, or tolerogenic, leading to silencing as is desirable in transplantation,

autoimmunity and allergy. To date, the successes of immunology in the clinic have largely been

based on antibodies made by B cells, but T cell-mediated immunity, which has enormous yet

untapped therapeutic potential will be stressed here.

DCs are specialized to capture and process antigens in vivo10-14, converting proteins to

peptides that are presented on MHC molecules and recognized by T cells. DCs also migrate to T

cell areas of lymphoid organs where the two cell types interact to bring about clonal selection15-17.

The DC system is thus designed to harness the recognition repertoire of T cells, consisting of

billions of different lymphocytes, each with a distinct but randomly arranged antigen receptor18.

This repertoire in turn represents a virtually infinite “drug library” for specific therapies that

increase or decrease T cell function.

Following clonal selection, DCs control many T cell responses. Antigen-selected T cells

undergo extensive expansion, a thousand fold or more as a result of division at a rate as high as

2-3 cell cycles a day19,20. Clones of lymphocytes are also subject to silencing or tolerance by so-

called “tolerogenic DCs”21-23, which either eliminate (delete)19,20,23-26 or block (suppress) T

cells27-39. If deletion is avoided, the clone undergoes differentiation to bring about an array of

potential helper, killer, and suppressive activities. For example, under the control of DCs, helper

T cells acquire the capacity to produce powerful cytokines like interferon-γ to activate

macrophages to resist infection with facultative and obligate intracellular microbes (Th1 cells)40-

44, or IL-4, 5 and 13 to mobilize white cells that resist helminths (Th2 cells)45,46, or IL-17 to

mobilize phagocytes at body surfaces to resist extracellular bacilli (Th17 cells)47-51.

Alternatively, DCs can guide T cells to become suppressive by making IL-10 (Tr1 cells)28,30,52,53

or by differentiating into foxp3+ cells36,37,39. Finally, DCs induce the T cell clone to acquire

memory, allowing it to persist for prolonged periods and to respond rapidly to a repeated

exposure to antigen54-58.

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There are four specialized features (Fig 2) of DCs that contribute to their capacity to

control T cell recognition and responsiveness and in turn, either prevent or generate disease.

Recent advances in DC biology are outlined in Boxes 1-4. Briefly, 1) DCs are positioned to

capture disease-causing antigens and to present these to lymphocytes in lymphoid organs12,59-64,

the sites for the generation of immunity and tolerance. 2) DCs have an endocytic system that is

dedicated to antigen capture and processing, creating ligands for different classes of

lymphocytes13,14. 3) DCs differentiate or mature in response to a spectrum of stimuli14,65,66

(Table 1), allowing them to bring about innate and adaptive responses that are potent and

qualitatively matched to the disease causing agent. 4) DCs are comprised of subsets that differ

from one another in terms of location, antigen presentation, maturation and development67-72.

Location (Box 1) and antigen presentation (Box 2) allow DCs to efficiently select specific clones

from the diverse recognition repertoire. Maturation (Box 3) and subsets (Box 4) allow DCs to

control the diverse response repertoire of T cells and other classes of lymphocytes such as B cells

and NK cells.

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Dendritic cells in infectious diseases

DCs induce resistance to infection. When microbial antigens are injected in association with

DCs into mice, the animals acquire adaptive immunity to Borrelia burgdorfei73, chlamydiae74,

Leishmania major75-77, fungi78,79, toxoplasma gondii80-82, malaria83, and HIV84,85. Conversely,

DC depletion reduces defenses to viruses like CMV86,87, HSV-288 and LCMV89. In humans, a

lack of circulating DCs during bacterial sepsis and dengue virus infection is associated with a

poor prognosis90,91.

A key concept is that DCs mature in distinct ways in response to different microbial

components, thereby launching alternative versions of host immunity. The microbial ligands act

on pattern recognition receptors5,7,8 including externally disposed toll like receptors6,44,92-94 and

lectins95,96, and the cytoplasmic NOD/NALP family 97-99, RIG-I and mda5 molecules100. These

pattern recognition receptors can function synergistically44,101-104.

In contrast, several microbes have the capacity to actively block DC maturation, e.g.,

Coxiella burnetti105, Salmonella typhi106, Anthrax lethal factor protein107, Plasmodia108, a M.

ulcerans mycolactone109 and viruses like vaccinia110, herpes simplex111,112, HIV113,114, CMV115-

118, varicella zoster119, HCV120,121, Ebola/Marburg/Lassa fever122,123, and measles124. An

interesting exception is the effective attenuated yellow fever virus vaccine that may work by

infecting and maturing DCs, allowing for antigen presentation to T cells125,126.

Furthermore, pathogens can alter other levels of DC physiology to evade an immune

response. For example, the agents of plague, Yersinia pestis, and typhoid fever, Salmonella typhi,

selectively inject toxins into phagocytes, including DCs, and destroy the cells required for innate

and adaptive protection127,128. Influenza, measles and HSV-2 can induce apoptotic cell death in

DCs112,124,129-131. With some viruses, cell death occurs through the intermediate formation of

giant cells or syncytia132-136. CMV, herpes and M. tuberculosis inhibit the migration step of DC

function by blocking expression of CCR7137-139, a chemokine receptor that guides DCs into

lymphatic vessels and onwards to lymphoid tissues15,17(Box 1, next page).

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Box 1, Location of DCs. DCs are a uniquely positioned, prime target for disease relevant stimuli. DCs are abundant at body surfaces like skin, pharynx, upper esophagus, vagina, ectocervix, and anus419, and at so called internal or mucosal surfaces, such as the respiratory and gastro-intestinal systems61,62,364,420-423. DCs actually extend their processes through the tight junctions of epithelia, which likely involves DC expression of the tight junction proteins claudens and occludens, without altering epithelial barrier function424. This increases DC capture of antigens from the environment61,163 even when there is no overt infection or inflammation, probably allowing for the silencing of the immune system to harmless environmental antigens26,363.

DCs at body surfaces can function locally, e.g., to convert vitamins A and D to active retinoic acid and 1,25(OH)2D3. One consequence of the overlooked metabolic capacities of DCs is to increase the homing of immune cells to that mucosal surface425-

427 and, in the case of retinoic acid, to help DCs differentiate suppressor T cells that block autoimmune and inflammatory conditions428-431.

After leaving peripheral tissues, DCs migrate with environmental, self, and microbial antigens to lymphoid organs, a process that is guided by chemokines15,17 and can be enhanced by vaccination432,433.

DCs have now been studied in intact lymphoid tissues without the need for cell isolation. These are the sites where immune resistance and tolerance are initiated. The DCs create a labyrinthine system within T cell areas, while probing the environment through the continuous formation and retraction of processes63 and displaying antigens and other stimuli needed to initiate responses by appropriate clones of specific T cells434-438. New research reveals interactions of DCs in lymphoid tissues with other major classes of lymphocytes, B cells423,439-448 and NK cells257,260,261,449.

Microbes also can alter the function of DCs so that they switch T cell responses from

protective Th1 to nonprotective Th2, as in infections with Aspergillus fumigatus140,141 malaria142,

and hepatitis C143, or to IL-10 production in the case of Bordetella pertussis144.

At this time, there are no therapies that try to interrupt the microbial immune evasion

pathways that are summarized above.

Several microbes additionally can exploit DCs for purposes of replication and spread in

the infected host. The lectin DC-SIGN/CD209 is used by dengue virus145,146 and Ebola virus147

to infect DCs. In the case of HIV-1, CMV, and Ebola virus, the lectin additionally sequesters

virus within DCs, which later transmit infectious virus to other targets like T cells147-153. DCs are

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also implicated in the spread of varicella zoster154, measles virus155, poliovirus156, Aspergillus

fumigatus157,158, LCMV159, Toxoplasma gondii 160, prions161, Listeria monocytogenes 162, and

Bacillus anthracis spores163.

Box 2, Antigen presentation by DCs. DCs contain a specialized endocytic system450, having many uptake receptors that deliver antigen to processing compartments14,68,451-

458. DCs then present peptides from processed proteins to CD4+ and CD8+ T cells454,459, self and microbial glycolipids to NKT cells460-462, and native antigens to B cells440,463,464.

Many uptake receptors on DCs are lectins with carbohydrate recognition capacity95,96. Some, like DEC-205/CD205 and mannose receptor/CD206179,312, are type I transmembrane proteins with multiple contiguous lectin domains451. A majority to date, such as DC-SIGN/CD209465, Langerin/CD207466, ASGPR467, LOX-1178 and DCIR68,468, are type II proteins with a single external lectin domain. Among these, CD209 has attracted wide interest because it binds a number of microbes including HIV148, dengue145, cytomegalovirus150, mycobacteria469,470 and candida471, and because it can hinder DC maturation and contribute to immune evasion472-474. Another lectin, Langerin/CD207, is reported to degrade HIV in DCs, thereby reducing transmission to T cells475.

Early literature on DCs took antigen uptake for granted, without realizing that ligation of uptake receptors increases the efficiency with which antigens are delivered to the immune system in vivo by ~100 fold19,56,176,476. Targeting vaccines to these DC receptors should significantly improve the efficacy of T cell mobilizing vaccines.

Following uptake of antigen, DCs are able to “cross present” antigens on MHC I to elicit CD8+ killer T cells235,263,307,476-482. During cross presentation, nonreplicating protein antigens are internalized and somehow gain access to the cytoplasm before being processed by the proteasome for peptide presentation on MHC class I. Critical steps seem to occur from less acidic compartments456,458. Cross presentation allows DCs to induce CD8+ T cell responses to immune complexes, nonreplicating forms of microbes and vaccines, and dying cells205,206,287,299,482,483.

For dying cells60,242,243,390,484, DC receptors for uptake remain to be defined in situ. Since cell death accompanies infection420, cancer246,248, transplantation390,391, the normal turnover of self tissues485, and some viral vaccines486, the uptake of dying cells is a starting point for DCs to capture antigens in many clinical settings. Fc receptors, which recognize antigen-antibody complexes, mediate antigen uptake and both activating and inhibitory signals in DCs204,205,207,487,488. For example, if inhibitory receptors are blocked, the binding of tumor cells coated with antibody leads to improved presentation of tumor antigens and production of the immune stimulating cytokine IL-12207,209.

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All these consequences of the microbial-DC interaction have been analyzed on myeloid

DCs, mainly in tissue culture but not in patients. We expect that microbes also evade and exploit

plasmacytoid DCs, which also help to resist pathogens164 and are diminished in the blood during

infections with HIV165-169, HTLV-1170 and RSV171.

Box 3, Maturation of DCs. DCs differentiate or mature in distinct ways in response to a spectrum of environmental and endogenous stimuli (Table 1). The maturation pathway then helps to designate which lymphocyte functions will be induced and which products will be made by both DCs and lymphocytes66,489-492.

In the steady state in the overt absence of maturation stimuli, DCs can induce tolerance when they capture self and environmental antigens19,23,363. Maintenance of tolerance can require PD-L125 as well as fas493 on DCs. Upon infection or other causes of maturation, the DCs redeploy, but it is still not understood why DC differentiation is so rapid and extensive. One factor may be the high levels of required NF-κB family proteins494,495 with each family member (s) able to control different DC responses496.

Maturing DCs can induce different types of CD4+ T cells (see text), such as Th192,93,497, Th245, or Th1748,51,498-502 to increase resistance. Other stimuli can yield “tolerogenic” DCs, which induce Tr1 and foxp3+ T regs28,33,35-37,52,356,361,503-509 to silence immunity. Maturing DCs also express more IL-15 and activate inflammation and NK cells in vivo261,510

When DCs mature in response to microbial products, expression of hundreds of genes is altered511,512, leading to synthesis of cytokines, e.g., IL-12 and type I interferons that enhance innate and adaptive resistance86,513-519. While cytokines in turn can induce some components of DC maturation, the DCs that directly interact with microbial ligands are the immunologically more active ones520,521. The types of cytokines are influenced by the DC subset and the mode of DC activation522-524. Several chemokines are also secreted in groups at a time525, attracting different cells in succession to the site of DC maturation: phagocytes, memory lymphocytes, and naïve T cells526. Numerous mechanisms also dampen the DC response to microbial products185,527.

Maturation regulates antigen processing by lowering the pH of endocytic vacuoles, activating proteolysis, and transporting peptide-MHC complexes to the cell surface453,454,528. Importantly, maturing DCs remodel their surface, typically expressing many membrane associated costimulatory molecules243,520. These include members of the B7, TNF and Notch families529-532.

continued, next page

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Box 3, continued. A critical unknown is to define the changes in DCs that link innate to adaptive immunity in vivo533. The standard view that a combination of MHC-peptide (“signal one”) and high B7-2/CD86 is sufficient to drive T cell immunity is oversimplified. To influence T cell differentiation, DCs additionally need to produce cytokines like IL-12 and type I interferons, or membrane associated TNF-family receptors, like CD40243and lymphotoxin receptors534 and TNF family members, like CD70 to induce Th1176,535 and OX40L to induce Th2536.

To counteract these mechanisms for pathogenesis of infectious disease, DCs are now

being considered in the design of vaccines to prevent and treat infection by enhancing

immunogenesis. A new concept is to deliver vaccine antigens to specific receptors on DCs (Box

2), along with stimuli to control DC maturation. For example, microbial proteins are genetically

engineered into anti-receptor monoclonal antibodies, which then quickly and selectively target to

large numbers of DCs within intact lymphoid tissues19,56,172. The CD205 receptor on DCs in

human lymphoid tissues173,174 delivers antigen for processing onto both MHC class I and II,

increasing presentation efficiency >100 fold relative to nontargeted antigen. Th1 responses,

considered valuable for protection against many intracellular pathogens and tumors, also are

induced when antigens from HIV, malaria, Leishmania and tumors are targeted to maturing

CD205+ DCs56,172,175,176. Significantly, these responses are broad, i.e., capable of recognizing

many peptides from a given microbial protein and in several MHC haplotypes56,177, and the

responses take place at mucosal surfaces, both key criteria in vaccine design. Other potential DC

targets are being addressed including LOX-1178, MMR179,180, DCIR68, DC-SIGN181, toxin

receptors182,183 and CD40184.

Beyond the value of antigen targeting, there is a need to mature DCs during vaccination

in a way that is appropriate to the pathogen at hand. Here, one needs to define correlates of

immunogenicity in vivo, i.e., what specific changes in DCs are required to generate protective

responses from the response repertoire?

Dendritic cells in cancer

DCs are found in tumors in mice185 and patients186. Yet tumors suppress immunity, especially

locally and by many pathways187-189. Tumors express cytokines, like IL6190,vascular endothelial

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growth factor191 and IL-10192, which suppress DCs through STAT3 signaling193,194. Tumors may

condition local DCs to form suppressive T cells, such as foxp3+195 and IL-13 producing CD4+

T196 and NKT197 cells. DCs even support the clonogenic growth of tumors in multiple

myeloma198. Therefore, like some infections, cancers have ways to evade and exploit DCs199.

Nevertheless, immunology is providing treatments for cancer, mainly in the form of

monoclonal antibodies200,201. Antibodies, by virtue of their antigen binding variable Fab regions,

can block critical functions on cancer cells202; and by virtue of their constant or Fc regions,

antibodies can mobilize an attack by other Fc receptor (FcR) bearing cells such as innate

phagocytes and NK cells203,204. Antibodies mediate the uptake and processing of tumor cells by

DCs and also can trigger DC maturation (Table 1)205-210. This portends the design of antibodies

that harness select FcRs to induce better innate and adaptive anti-tumor immunity.

More emphasis is needed on cell mediated immunity that also has a clear capacity to

resist cancer211,212. In phase I clinical research, adoptive transfer of killer T cells leads to

regressions of melanoma and other cancers213-216. There is also a major survival benefit from

allogeneic bone marrow transplantation, in which lymphocytes from the marrow donor resist

leukemia and other hematologic malignancies (the “graft vs. leukemia” reaction)217-220. In

multiple myeloma, T cells that recognize glycolipids and peptides in the tumor are found in a

premalignant stage of disease but not when the tumor grows out of control221,222. In

paraneoplastic diseases, T cells respond to antigens shared by the tumor and the nervous system,

and likely resist the tumor but at the same time cause severe neurologic sequelae223.

Examination of colorectal cancers indicates that the presence of a Th1 type immune response in

the tumor correlates with a better prognosis224,225. On the other hand, immune suppression

predisposes to higher frequencies of several cancers226. All of the above examples imply a role

for immune surveillance by T cells against human cancer, as is also seen in mice227,228.

DCs can be marshaled for the prevention and treatment of cancer for the following

reasons229. 1) Tumors are replete with potential antigens230-232, and they can become

immunogenic when presented by DCs229,233-238. This means that the immune attack on cancer

can be broad enough to encompass multiple targets including mutant proteins expressed by the

cancer, and not just one target, where the latter favors immune escape. 2) Likewise, DCs can

activate and expand the different arms of cell-mediated resistance such as NK239,240, NKT221,241-

244, γδ T245 and αβ T227,246-248 cells, each of which recognizes different alterations in cancer cells.

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3) DCs in systemic lymphoid organs and DCs generated ex vivo from progenitors in blood likely

retain their immunizing capacities in cancer patients43,247,249-254. Therefore one can test whether

the specific features of DCs (Fig. 2) can be harnessed either to generate therapeutic immunity or

to prevent cancer during premalignant or minimal residual disease stages255,256.

Two DC based immune therapy approaches are currently available. In one, DCs are

generated ex vivo, loaded with tumor antigens, and reinjected to take advantage of the ability of

DCs to migrate to the T cell areas of lymphoid organs to induce strong T cell and perhaps NK

immunity257-261(Fig. 3). Less explored is the evidence that DCs themselves can acquire killer

activity for human tumors and express granzyme and perforin killer molecules262. In another

strategy, tumor cells or tumor antigens are targeted directly to DCs in the T cell regions (Fig 3),

e.g., within monoclonal anti-DC antibodies as discussed above.

Already a large number of phase I studies in humans have used the first approach in

which DCs are generated from precursors ex vivo. These early trials have only occasionally

yielded significant tumor regressions263-265, and there are no studies yet showing improved

survival.

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The current deficiencies in DC therapy need to be addressed in patients to deal with

significant scientific and other obstacles. First, DC vaccines are being tried only in late stage

cancer patients who are immunosuppressed as a result of extensive radiation, chemotherapy

and/or large tumor burdens. Why limit research to these patients, especially when DC therapy is

nontoxic, including in the few patients who have experienced major tumor regressions263-265?

Second, most injected DCs remain at the injection site. Only a few migrate to the draining

lymphoid tissue, ~ 1 % in mice and humans266,267. Research in patients will be required to

overcome this limitation. One example is to condition the injected site with cytokines like TNF,

so that the injected DCs receive needed cues for migration into lymphatics268. Third, more

emphasis is needed on DC quality, by testing DCs for their capacity to induce helper and killer T

cells with a high avidity for tumor antigens but few T regs269-271. Fourth, many initial vaccine

studies used DCs charged with one or a few tumor antigens, whereas the potential of DCs rests

with their still untapped capacity to elicit a strong and broad immune attack to lessen the chances

of tumor escape. Fifth, vaccine studies need to be accompanied by in depth immune monitoring

to define assays for protective lymphocytes whose presence correlates with tumor regression

and/or improved survival. For example in HIV vaccines, it is thought that protective T cells will

produce several and higher levels of cytokines like IFN-γ, IL-2, and TNF-α272,273; express low

levels of the PD-1 regulatory protein274-276; and have high functional avidity for antigen277. Sixth,

DC based immune therapies require a coordinated research effort to generate DCs for clinical use

and to help investigators systematically evaluate the many variables pertinent to efficacy278.

Even with these limitations, early trials with ex vivo DCs have in patients with advanced

cancer expanded T cells that recognize multiple tumor antigens279 and make the protective

cytokine, IFN-γ43,280,281. These observations provide a starting point to use DCs in a more

concerted way to study their immune capacities in cancer patients, and to combine immunization

with other therapeutic modalities282. Chemotherapy283-287, radiotherapy288, and removal of tumor

regulatory mechanisms, e.g., CTLA4289,290, B7-H4291,292, IL-10293,294, TGF-β195,295, IL-13196,197,

could be more specific and less toxic if combined with DC-based therapies.

The ex vivo technique is being developed so that it is easier to carry out, including in

collaborative studies296-298. This approach allows the basic features of DCs (Fig. 2) to be

controlled, e.g., to load them appropriately with multiple antigens including tumor

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cells263,265,299,300 tumor RNA301, or potentially cancer stem cells302; to select from many options

for DC maturation300,303,304(Box 3); and to specify the DC subset for clinical use 279(Box 4).

Box 4, Subsets of DCs. There are several types of DCs, each with distinct markers and functions69. Plasmacytoid DCs, so named because of cytologic similarities to antibody-producing plasma cells537-539, can be involved in tolerance in their immature state540. For maturation, these DCs selectively express activating FcR209,210 as well as TLR7 and TLR9328,457,541-544. When immune complexes containing DNA and RNA are bound and ingested, they signal potentially pathologic levels of type I interferons323,327-

329,331. Other DCs, termed “myeloid,” also produce type I interferons515,545,546.

Myeloid DCs in different tissues can be further subdivided based on expression of certain markers and functions. In the case of skin, DCs in the epidermis (Langerhans cells) express Langerin/CD207547 and DEC-205/CD205, and induce strong killer T cell responses548; some DCs in the dermis express DC-SIGN/CD209 and mannose receptor/CD206549 and can activate antibody forming B cells550. Distinct skin DC populations also migrate to different areas of the draining lymph nodes551,552. Thus the outcome of skin vaccination may depend on the lectin and DC subset that pick up the vaccine.

In mouse spleen, a DC subset expresses DEC-205 and is particularly efficient for the cross presentation of antigens on MHC I60,67,68,478,481,553, including tumor cells248, and also for the induction of IFN-γ producing, Th1 helper T cells41,42,176. A second subset expresses DCIR2 and other lectins and is more efficient at processing antigens for presentation on MHC II68. In lymph nodes draining mucosal tissues, the presence of an integrin, CD103, distinguishes a DC subset that cross presents on MHC class I554 but also synthesizes retinoic acid for the differentiation of foxp3+ T reg428-430.

DC subsets communicate with each other, e.g., plasmacytoid DCs produce interferons and membrane bound costimulators that recruit other DCs to participate in immunity555,556. The production of most DC subsets is controlled in the steady state by the cytokine, flt-3 ligand557,558, whereas during inflammation and infection, another cytokine GM-CSF mobilizes increased numbers of monocyte-derived DCs559-564. In the steady state, DCs in lymphoid tissues emanate from marrow progenitors in the blood565,566 but not monocytes567,568, although monocytes give rise to DCs in some nonlymphoid tissues in the steady state568 and in many sites during inflammation69.

A second DC-based strategy in cancer therapy would be to mobilize DCs directly within

the patient, either within the tumor or within lymphoid organs. In mice, irradiated tumor cells

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injected intravenously are taken up by DCs60,248. Alternatively, one can inject irradiated tumor

cells that are transduced to express GM-CSF, which recruits the patient’s DCs to capture and

present tumor antigens305-308. A new approach to the maturation of antigen capturing DCs in

vivo uses innate NKT cells that recognize glycolipids309. The activated NKT cells mimic the

effects of a combination of TLR and CD40 ligation on DCs and elicit long lasting, protective

CD4+ and CD8+ T cell resistance248,310,311. Another example is to selectively target cancer

antigens within monoclonal antibodies to receptors on DCs175,312, thus ensuring the delivery of

antigen to large numbers of DCs in the T cell areas of lymphoid organs, as opposed to the small

numbers that successfully home from an injection site to these areas (Fig. 3).

Unfortunately, DC-mediated immunization against cancer is still an underdeveloped field.

Yet this approach can exploit the patient’s responses to cancer to produce more specific, less

toxic, broader, and longer lasting therapies. There is an important unmet need to expand and

coordinate research on DC based therapies against proliferating and initiating cancer cells.

Dendritic cells in autoimmunity

Inappropriate responses to self constituents, in select genetic backgrounds, can lead to chronic

inflammatory conditions, termed autoimmune diseases. DCs bearing self antigens are able to

induce autoreactive T cells in mouse models of multiple sclerosis313, cardiomyopathy314,315, and

systemic lupus erythematosus (SLE)316.

It is increasingly appreciated that a pivotal step leading to human autoimmunity is an

overproduction of a particular cytokine(s)317-320, and subsets of DCs can be a major source. For

example:

• TNFα is a key cytokine in rheumatoid arthritis and other diseases, like psoriasis,

and TNFα blockade is a powerful therapy for many patients321. In psoriasis, a

major source of TNFα is a DC subset infiltrating the affected skin322.

• Lupus erythematosus, a systemic disease in which antibodies are formed against

self constituents especially nucleoproteins, is accompanied by what is termed an

interferon signature in white blood cells323. Type I interferon is made in large

amounts by plasmacytoid DCs324,325, which infiltrate the skin lesions of SLE326.

Viral nucleic acids, as well as self nucleoproteins internalized in the form of

immune complexes, trigger TLR7 and TLR9 leading to type I interferon

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production327-329. Moreover, the DNA binding protein and cytokine, HMGB1,

can deliver self DNA to TLR9 and ligate the RAGE receptor on DCs330.

Interferon in turn drives the mobilization of activated granulocytes323 and

differentiates monocytes into DCs, which may present dying cells in an

immunogenic rather than tolerogenic manner331. Ligation of activating FcR by

the immune complexes that are formed during autoimmunity also drives DC

maturation209,210,332.

• Type I interferon and plasmacytoid DCs are also proposed to be pathogenic in

such other diseases as psoriasis333, dermatomyositis334, and Sjogren’s syndrome335.

• IL-23336 is a cytokine that drives disease, including psoriasis and inflammatory

bowel disease337-341, and DCs are major IL-23 producers342-344.

Despite their role in inducing autoimmunity, DCs are also relevant to the therapy of these

diseases. 1) Various treatments especially glucocorticosteroids can reduce DC numbers and

functions323,345-352. 2) Since DCs seem to be a source of pathogenic cytokines, the stimuli for

cytokine production need to be identified and obviated. 3) One potential antigen-specific

strategy relates to the capacity of DCs to expand and induce T cells that suppress immunity,

usually termed “T regs”31,33,37,353-358. T regs can suppress other DCs that present disease

producing antigens359,360. In the case of a spontaneous model of autoimmunity, diabetes in NOD

mice, T regs that recognize antigens in insulin producing β cells can be generated by DCs and

provide a therapeutic benefit even after the onset of disease36,361.

Dendritic cells in allergy

DCs normally tolerize the immune system upon exposure to harmless environmental

antigens22,34,362,363, including the pollens, dust mites, and foods that cause respiratory and

intestinal allergy. The DCs at mucosal surfaces capture proteins364 and silence the corresponding

T cells, possibly by expressing ICOS-L, which in turn differentiates antigen-specific, IL-10

producing T regs365,366. In allergy, instead of this immune tolerance, CD4+ helper T cells

develop along the atopic Th2 pathway and yield interleukins (IL-4, 5, 13) responsible for many

aspects of disease, such as the formation of IgE type antibodies. DCs both initiate the formation

of proallergic Th2 T cells and boost symptom-producing responses in already allergic mice367-371.

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How might the normal tolerizing roles of DCs be altered during allergy? Cytokines may

again be pivotal, e.g., recent studies reveal a role for thymic stromal lymphopoietin (TSLP)372 in

atopic dermatitis46,373 and asthma374. TSLP matures human DCs from blood46 and skin375 to

elicit unusual Th2 cells that secrete not only IL-4, 5, and 13 but also high levels of TNF. TSLP-

treated mature DCs express OX40L, a TNF family member. OX40L can instruct T cells to

develop a Th2 type of memory along with the production of allergic mediators like prostaglandin

D257,376.

Several new directions for allergy research involve DCs. 1) DC maturation by TSLP

needs to be understood and blocked; likewise for TSLP production by epithelial cells, which is

controlled by retinoid receptors377 as well as IL-1 and other inflammatory cytokines378. 2) The

substances that cause allergy may modify DC function directly by blocking IL-12 production by

DCs and in turn favoring formation of allergic Th2 cells379. 3) In humans, new synthetic

oligonucleotides can suppress the presentation of allergens by DCs to Th2 cells380; these

compounds have shown promise in treating ragweed induced allergic rhinitis381. 4) DCs might

be targeted to allow for formation of allergen-specific T regs, which can treat allergy as observed

in mouse models382,383. 5) New drugs can interfere with the pro-allergic functions of DCs and

treat experimental asthma384. The sphingosine-1-phosphate receptor agonist FTY720 blocks the

migration of DCs from lung to lymph nodes where the DCs could present antigens to disease-

causing Th2 cells385, while agonists for the D prostanoid 1 receptor condition DCs to induce

disease-reducing T regs386.

Dendritic cells in transplantation

DCs play a key role in the outcome of organ and hematopoietic transplantation. DCs in grafted

organs mature and migrate into the recipient387-389, where they stimulate alloreactive T cells that

bring about graft rejection. Recipient DCs also can capture portions of the graft390,391 and elicit

organ rejection. Interestingly, suppressive drugs in current clinical use may act on the rejection-

inducing DCs as well as the rejecting T cells392-396. In hematopoietic transplantation, recipient

DCs are key initiators of T cell-induced graft versus host reactions397,398. Mechanisms have yet

to be pinpointed to explain the maturation and migration of DCs that accompany transplantation.

It seems reasonable to propose that strategies to block these DC functions during

transplantation will promote acceptance399. However, recent discoveries show that DCs in

15

grafted tissues can regenerate locally400, thus providing a long term source of antigen to stimulate

rejection398. In this light, alternative pathways to use DCs to induce transplantation tolerance are

being assessed401-403. One involves the activation of recipient NK cells, which reject donor DCs

in tissue culture models404,405 and in vivo406. Another pathway is to induce DCs to become

tolerogenic389, e.g., to express the tolerogenic ILT3 molecule407 or to induce graft-specific foxp3+

T reg to suppress graft-rejecting T cells35,391. In hematopoietic cell transplantation, strategies

that lead to recipient DC depletion are currently being tested in the clinic.

Extending DC biology into medicine.

Immunology, including T cell mediated immunity, has a central role in understanding how

disease develops and in designing new treatments (Fig. 4). Here we suggest therapies aimed at

the upstream events initiated by DCs. DCs can either intensify or subdue T cell responses,

depending on whether resistance or tolerance needs to be increased.

Considerable evidence from studies in mice, which predominates in this review, shows

how DCs act in a disease specific manner. Increased emphasis on the antigens that elicit disease

should provide medical approaches that are longer lasting and less subject to side effects than

current antigen-nonspecific ones. To repeat, DC-based analyses and therapies emphasize initial

events in complex disease cascades, but more patient-based research is needed to take DCs into

medicine.

16

The scientific rationale is that a patient’s response to disease involves not only antigens

and lymphocytes but also DCs that control antigen presentation and clonal selection (the immune

recognition repertoire) as well as lymphocyte growth, differentiation and memory (the immune

response repertoire). Each feature of DCs in fig. 2 is an intricate area for research, whose

findings are facilitating a deeper analysis of disease and how to interrupt its progress. However,

major gaps exist to take this science into medicine.

In mice, the current research emphasis has been on model antigens, isolated DCs, and

highly selected populations of T cells with a single transgenic antigen receptor. Instead, research

on DCs needs to be directed to the control of immune responses 1) in situ in intact animals, 2)

within the natural immune repertoire, 3) to clinically relevant antigens, and 4) with new immune

enhancers or adjuvants that act in defined ways on DCs. Even so, the immune systems of mice

and men differ in many aspects408. A demanding subject, but one which will enhance disease

research, is the development of mice with immune systems derived from human sources196,409-416.

More research needs to be done with patients. The patient sets the standards for the

quality of knowledge that is required to understand many aspects of disease and its treatment.

Often the pathogen (tumor, microbe, allergen, stimulus for autoimmune or autoinflammatory

disease) is not easily or completely modeled in mice.

Although scientists and the public both desire “translation” from mice to humans, there is

an underappreciated need to create a sizeable limb of the scientific enterprise that will bring new

methods, concepts, and coordination to the basic study of disease with patients. This need is

illustrated by the paucity of DC-based studies on the immunotherapy of cancer. Basic research

with patients differs substantially from current outcome studies and drug licensing trials, which

test whether existing practices and concepts are clinically effective. In contrast, disease research

yields new ideas and therapies. The biology of DCs is ready to be extended to dissect disease

pathways and to direct its prevention and treatment. Despite the obstacles to research in

patients417,418, physicians and scientists have the knowledge and tools to think systemically about

diseases, plan their therapies, and investigate how human beings respond. DCs are an early

player in disease development and an unavoidable target in the design of treatments.

17

Acknowledgement. The authors thank Carol Moberg and Michel Nussenzweig for extensive

comments and Judy Adams for assistance with the manuscript. We are grateful to our patients

and colleagues for their many contributions, and to the NIH and several foundations for support.

18

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