Dendritic Cell Gene Profile

8/9/2019 Dendritic Cell Gene Profile

1/18

Abstract. Dendritic cells are potent antigen presenting cellswhose function has been associated with a variety of

immunological disorders. Because of their relevance tohuman disease, extensive efforts have been made to gain a better understanding of their biology. One aspect of theseefforts has been in the identification of pertinent moleculesexpressed in these cells through gene profiling experimentsand proteomics. In this review, we summarize the resultsfrom the various profiling studies that have been done withhuman dendritic cells. We focus on molecules, which havebeen confirmed by other methods, such as quantitative PCR,or have been identified in multiple profiling studies to beexpressed in the respective dendritic cell type. Through such profiling experiments and subsequent analysis, interestingmolecules have been identified which can be further studiedto determine their role in dendritic cell biology.

Key words: Dendritic cells Gene profiling Human

Introduction

Dendritic cells are generally acknowledged to be the mostpotent antigen presenting cell type known (as reviewed in [1,2]). One of the reasons for this is because of their ability toactivate T lymphocytes at effector: target ratios much lowerthan other types of antigen presenting cells, such asmacrophages and B cells. In addition to this property, den-

dritic cells are capable to activate a wider range of T cellsthan other known antigen presenting cells. In particular, theyare unique in their ability to activate nave T cells.

Because of these capabilities, in addition to others,increased dendritic cell activity has been associated a widerange of immunological based disorders, including asthma[3], rheumatoid arthritis [4], lupus [5], and multiple sclerosis[6]. Therefore, much effort has been investigated in learningmore about the biology of the dendritic cells. Some of thiseffort has focused on the profiling of genes expressed inthese cells. This has led to approximately 40 different profil-ing studies on dendritic cells, which is summarized for the

Inflamm. res. 53 (2004) 424 4411023-3830/04/090424-18DOI 10.1007/s00011-004-1283-z

human dendritic cells in Table 1. This review will focus onanalyzing what we have learned from such studies, primarily

focusing on the human dendritic cell types, and what addi-tional information can be gained from such studies.

Models used for dendritic cell profiling

Until approximately ten years ago, it was challenging to per-form studies on human dendritic cells because of the diffi-culty to isolate them. This changed with the development ofsystems for the differentiation of dendritic cells from pre-cursor cells that are easier to isolate [33, 34]. One of themore common methods for preparing dendritic cells is bythe differentiation of monocytes with IL-4 and GM-CSF toimmature dendritic cells. Although less common, CD34+

stem cells have also been used as a source for precursor cellsin dendritic cell profiling studies.

Overall, immature dendritic cells are defined as cells thathave a potent ability to take up and process antigen [1, 2].Immature dendritic cells are characterized by a number ofcriteria. First, is an increase in the ability of these cells to takeup antigen, commonly assayed by the uptake of FITC-coateddextran. Secondly, there is a characteristic morphologicalchange, from round shaped cells to an irregular cell shapewith spine-like projections. Lastly is the increase in cell sur-face markers, such as mannose receptor and HLA-DR, and adecrease in the expression other cell surface markers, such asCD14. Another criteria, which is used, but is more relevant to

the mature dendritic cell, is the ability of the dendritic cell topromote T cell proliferation through an alloreactive stimula-tion.

As shown in Table 1, a number of laboratories have usedGM-CSF/IL-4 treated monocytes as a method to preparedendritic cells for profiling. However, because of the variousmodifications used in this protocol, such as amount andsource of cytokine used, length of time for differentiation,and cell media used, each of these reports can give a differ-ent set of genes induced upon differentiation. Depending onthe report, as indicated in Table 1, one or more of the criterialisted in the previous paragraph are used to define the differ-entiated monocytes as being immature dendritic cells. Oneassumption is that although protocols may change, if the

Birkhuser Verlag, Basel, 2004

Inflammation Research

Understanding human dendritic cell biology through gene profiling

Z. Tang and A. Saltzman

Aventis Pharmaceuticals, Immunology Platform Department, Mail Stop G303A, Routes 202-206, Bridgewater, NJ 08807, USA, Fax: 908 231 3586

e-mail: [email protected]

Received 25 February 2004; accepted by A. Falus 14 April 2004

Correspondence to: A. Saltzman


2/18

Vol. 53, 2004 Human dendritic cell profiling 425

Table 1. Summary of published dendritic cell gene profiling and proteomics studies.

Reference Method for Characterization Method for Characterization Profiling Comparison donedifferentiation to/ of immature maturation/ of matured/ Assayisolation of dendritic cells treatment of treatedimmature immature immaturedentritic cells dentritic cells dendritic cells

Hashimoto S-I, et al. 1) Monocytes: Morphology, N/A N/A SAGE Comparison of 1999 [7] GM-CSF/IL-4/ cell surface monocytes/TNF-a+ 7.5% FCS markers immature dendriticin RPMI-1640 cells/macrophages2) Monocytes:GM-CSF 7.5% FCSin RPMI-1640(macrophages)

Dietz AB, et al. Monocytes: Cell surface IL-6/TNF-a/IL-1b/ Cell surface marker, Microarray Immature dendritic2000 [8] GM-CSF/IL-4 + 1% markers PGE2 (3 days) cytokine production, cells/mature dendritic

human plasma in T cell alloreactive cellsXVIVO-15 stimulation

Hashimoto S-I, et al. Monocytes: GM- Morphology, cell LPS (48 h) Morphology, cell SAGE Immature dendritic2000 [9] CSF/IL-4 + 7.5% surface markers surface markers cells/mature dendritic

FCS in RPMI-1640 cells

Angnieux C, et al. Monocytes: GM- Morphology, cell N/A N/A Differential Immature dendritic2001 [10] CSF/IL-4 + 10% surface markers display cells/monocytes

FCS in RPMI-1640 Proteomics

Baltathakis J, et al. 1) Monocytes: Cell surface LPS (48 h) Cell surface Microarray Mature dendritic cells/2001 [11] GM-CSF/IL-4+ 10% markers, T cell markers, T cell macrophages/

FCS in RPMI-1640 alloreactive alloreactive monocytes2) Monocytes: stimulation stimulationM-CSF+10% FCSin RPMI-1640(macrophage)

Bleharski JR, et al. Monocytes: GM-CSF/ Unknown CD40L (24 h) Cell surface cDNA Mature dendritic cell2001 [12] IL-4+ 10% FCS in markers, cytokine subtraction cDNA subtracted

RPMI-1640 production with immaturedendritic cell cDNA

Huang Q, et al. Monocytes: GM-CSF/ Cell surface 1)Escherichia coli Cell surface Microarray Immature dendritic2001 [13] IL-4 + 10% FCS in markers 2) Candida albicans markers cells/dendritic

RPMI-1640 3)Influenza cells matured with4) LPS respective individual5) Poly I:C agents at respective6) Mannan time points(1, 2, 4, 8, 12, 18,24, and 36 h for therespective stimulus)

Lapteva N, et al. Monocytes: GM-CSF/ Morphology, cell N/A N/A Microarray Monocytes/immature2001 [14] IL-4 + 10% FCS in surface markers dendritic cells

AIM-V

Lapteva N, et al. Monocytes: GM-CSF/ Cell surface a-galactosyl- Cell surface Microarray Treated/untreated2001 [15] IL-4 + 10% FCS in markers ceramide (48 h) markers dendritic cells

AIM-V

Lapteva N, et al. Monocytes: GM-CSF/ Morphology, cell TNF-a(48 h) Morphology, cell Microarray Immature dendritic2001 [16] IL-4 + 10% FCS in surface markers surface markers cells/matureAIM-V dendritic cells

Le Naour F, et al. Monocytes: GM-CSF/ Morphology, cell TNF-a(7 days) Morphology, cell Microarray and Monocyte/immature2001 [17] IL-4 in XVIVO-15 surface markers surface markers proteomics dendritic cells/mature

dendritic cells

Moschella F, et al. 1) Monocytes: Cell surface 1) TNF-a(48 h) Cell surface Microarray Immature dendritic2001 [18] GM-CSF/IL-4 in markers 2) CD40L (48 h) marker cells/dendritic cells

AIM-V 3) IFNg(48 h) matured with2) Monocytes: respective individualGM-CSF/IL-7 in agentsAIM-V


3/18

426 Z. Tang and A. Saltzman Inflamm. res.

Table 1. (continued)


Ahn JH, et al. 1) Monocytes: Morphology, 1) Monocyte Morphology, cell Microarray and 1) Microarray:2002 [19] GM-CSF-IL-4 + cell surface conditioned media + surface markers cDNA different dendritichuman serum in markers TNF-a(monocyte- subtraction cell types, immatureRPMI-1640 derived dendritic and mature and2) CD11c- cells) (2 days) CD34+ cells(plasmacytoid) 2) IL-2/ CD40L 2) cDNA Subtraction:dendritic cells) (in RPMI-1640 + Pool of samples3) CD34 + cells; 10% human serum) #2, 3, and 4TNF-a/IL-3 + human (plasmacytoid) (immature) cDNAserum in RPMI-1640; (5 days) subtracted withCD1a + CD14- sorted 3) Time of differen- cDNA from B cells,4) CD34 + cells; tiation (8 day vs monocytes, andTNF-a/GM-CSF + 18 days) (CD1a + T cellshuman serum in CD14-sorted)RPMI-1640; 4) Time of differen-CD1a-CD14 + sorted tiation (8 day vs

18 days) (CD1a CD14 + sorted)

Lapteva N, et al. Monocytes: GM-CSF/ Morphology, cell 1) Angiotensin II Cytokine Microar ray Immature dendritic2002 [20] IL-4 + 10% FCS in surface markers (6 h) production cells untreated and

AIM-V 2) Captopril (6 h) treated withrespective agent

Lindstedt M, et al. Monocytes: GM-CSF/ Morphology, cell Monocyte Morphology, cell Microar ray Immature dendritic2002 [21] IL-4 + 10 % FBS in surface markers conditioned media + surface markers cells/dendritic cells

RPMI-1640 TNF-a/IL-1b matured at respective(8, 24, and 48 h) time points

Matsunga T, et al. Monocytes: GM-CSF/ Cell surface 1) LPS Cell surface Differential Immature dendritic2002 [22] IL-4 + 10% FCS in markers 2) TNF-a markers display cells/dendritic cells

RPMI-1640 3) TGF-b matured with(1, 4, and 24 h) respective individual

agents at respectivetime points

Rissoan M-C, et al. 1) Plasmacy-toid Unknown 1) IL-3/CD40L Unknown cDNA a) Pool of plasmacy-2002 [23] dendritic cells isolated (plasmacytoid) (24, subtraction toid dendritic cell

from tonsil 48, 72, and 96 h) cDNA (both CD40L2) Monocytes: 2) CD40L treated and untreated)GM-CSF/IL-4 + 10% (monocyte derived subtracted withFCS in RPMI-1640 dendritic cells) mature monocyte

(16 and 48 h) derived dendritic cellcDNAb) Immature plasma-cytoid dendritic cellcDNA subtractedwith immaturemonocyte deriveddendritic cell cDNA

Schlaak JF, et al. Monocytes: GM-CSF/ Unknown IFN-a2a (8 h) Unknown Microarray Treated/untreated2002 [24] IL-4 + 10 % FCS in dendritic cells

RPMI-1640

Chaussabel D, et al. 1) Monocytes: Cell surface Parasites (16 h): Cell surface marker Microarray Dendritic cells and2003 [25] GM-CSF/IL-4 + 10% markers 1)Brugia malayi macrophages treated

human serum in 2) Toxoplasma and untreated withRPMI-1640 gondii respective individual2) Monocytes: 3)Leishmania agentsM-CSF+10% human majorserum in RPMI-1640 4)Leishmania(macrophage) donovani


4/18


immature dendritic cells isolated share the same properties(i.e., antigen uptake ability), then the same genes relevant forthis function should be equally regulated. However, sincesome of these properties are not universally tested prior toprofiling, this type of assumption has a certain level of risk.

Maturation of immature dendritic cells is defined as theirincreased ability to present antigen and activate T cells [1, 2].Consequently, accessory molecules necessary for this T cellactivation ability, such as CD80 and CD86, are upregulatedon the surface of the mature dendritic cell. Furthermore, as

their ability to present antigen is induced upon maturation,the ability of dendritic cells to take up antigen is decreased.Therefore, the cell surface expression of molecules relevantin this process, such as the mannose receptor and DEC205, isdecreased. Maturation of dendritic cells occurs through theirinteraction with infectious agents, cytokines, or contact withother cell types. Infectious agents or components from suchagents used for profiling studies include LPS [9, 11, 13, 22,26, 29] poly I:C [13], bacteria (e.g.,Escherichia coli) [13],yeast (e.g. Candida albicans) [13], parasites (e.g. Leishma-



Hashimoto S-I, et al. 1) Monocytes: Morphology, cell LPS (48 h) Morphology, cell SAGE Comparison of 2003 [26] GM-CSF/IL-4 +7.5% surface markers (monocyte derived surface markers immature dendriticFCS in RPMI-1640 dendritic cells) cells, mature2) Monocytes: dendritic cells,GM-CSF/IL-4/ langerhans-like cells,TGF-b+ 7.5%FCS in unstimulated, mono-RPMI-1640 cytes, LPS stimulated(Langerhans like-cells) monocytes, unstimu-

lated macrophages,LPS stimulatedmacrophages, naveCD4 positive T cells,memory CD4 positiveT cells, TH1 cells,TH2 cells, NK cells,unactivated B cells

and activated B cellsIzmailova E, et al. Monocytes: Morphology, cell 1) HIV-1 infection TAT mRNA Microarray Untreated/HIV-1/2003 [27] GM-CSF/IL-4+ 10% surface markers (1, 3, and 10 days) expression, TAT-adenovirus/

FCS in RPMI-1640 2) TAT-adenovirus cytokine control infected(4, 10, 16, and 30 h) production dendritic cells at

given time points

Ju X-S, et al. CD34+ cells; Morphology, cell TNF-a(6 days) Morphology, cell Microarray Progenitor/2003 [28] GM-CSF-IL-4 + 10% surface markers, surface markers, immature dendritic

FCS in RPMI-1640 endocytosis, endocytosis, T cell cells/matureT cell alloreactive alloreactive dendritic cellsstimulation stimulation

Messmer D, et al. Monocytes: Cell surface 1) LPS (24 and 48 h) Cell surface Microarray Immature dendritic2003 [29] GM-CSF/IL-4 + 1% markers 2) CD40L (24 and marker, cytokine cells/dendritic cells

human plasma in 48 h) production matured withRPMI-1640 3) IL-6/TNF-

a/ respective individual

IL1b/ PGE2 (24 agents at respectiveand 48 h) time points

Moschella F, et al. 1) Monocytes: Cell surface N/A N/A Microarray Dendritic cells2003 [30] GM-CSF/IL-4 in markers, T cell differentiated under

AIM V medium alloreactive respective protocol2) Monocytes: stimulationGM-CSF/IFN-a2b inAIM-V

Skelton L, et al. Monocytes: Morphology, cell Monocyte Morphology, cell Microarray Immature/mature2003 [31] GM-CSF/IL-4 +10% surface markers, conditioned media surface markers, dendritic cells

FCS in RPMI 1640 endocytosis, (72 h) endocytosis, T cellT cell alloreac- alloreactivetive stimulation stimulation

Treci , et al. Monocytes: Cell surface CD40L (2 and Cell surface marker Microarray Immature dendritic

2003 [32] GM-CSF/IL-4 + 10% markers 40 h) cells/matureFCS in RPMI-1640 dendritic cells


5/18

nia major) [25], and viruses (e.g. influenza virus, HIV-1) [13,27]. Cytokines and molecules reflecting cell-cell contact thathave been used to mature dendritic cells for profiling studiesinclude TNF- [8, 1619, 21, 22, 28, 29] and CD40L [12,18, 19, 23, 29, 32].

Although the ultimate definition of maturation, ability topresent antigen and activate T cells, is achieved by all of these

maturation agents, the signaling mechanisms involved arequite different. Thus, stimulation of dendritic cells withinfectious agents would activate receptors and intracellularsignaling pathways associated with innate immunity, such astoll-like receptors (TLR) [35, 36] quite different from thepathways activated by TNF- [37]or CD40L [38]. For exam-ple, unlike TNF- or CD40L, TLR stimulation can directlyactivate IRF3 leading to type 1 interferon induction [39].Furthermore, the pathways stimulated by the particular infec-tious agent diverge amongst the different TLR activated.Thus, while the stimulation of TLR4 or TLR5 in dendriticcells can lead to the activation of p38 and JNK1/2 and thesubsequent induction of IL-12 production, TLR2 stimulation

induces the activation of ERK1/2, leading to the suppressionof IL-12 production [40].Another consideration is the context in which the stimu-

lation occurs. For example, CD40L stimulation would mostlikely occur in the draining lymph nodes when dendritic cellsare interacting with nave T cells, unlike where infectiousagent or TNF- induced maturation would occur. Althoughthe primary response, induction of T cell activation capaci-ties, would be induced in both circumstances, other proper-ties (for example types of chemokines induced) would bepredicted to be different due to the environment where theresponse is taking place.

In addition to in vitro models for dendritic cell profiling,recently, taking advantage of the cumulative knowledge in

the identification and isolation of dendritic cells produced invivo, profiling studies have been initiated with these isolateddendritic cell types [19, 23]. There are two types of humandendritic cells that have been identified from blood, aCD11c, CD123+plasmacytoid and a CD11c+, CD123 mye-loid dendritic cell type [41]. The plasmacytoid dendritic cellsare potent antigen presenting cells [41, 42]. They are bestknown for their capacity to produce high levels of interferon upon stimulation [43], unlike myeloid dendritic cells. Theyare also distinguished from myeloid dendritic cells by theirexpression of distinct TLR , primarily TLR7 and TLR9, inwhich the latter is activated by CpG motif containing DNAmolecules [44]. Plasmacytoid dendritic cell are increasing

being considered playing a role in the antiviral responses andin diseases associated with high levels of type I interferons,such as lupus [45]. The myeloid class of dendritic cells moreclosely represents the dendritic cells that are obtained bythe differentiation of precursor cells with GM-CSF/IL-4[41]. They have a strong ability to take up, process, and present antigen [41]. They express TLR distinct from theplasmacytoid dendritic cells, in particular TLR2 and TLR4[44]. Thus myeloid dendritic cells, unlike plasmacytoid den-dritic cells, are capable of being stimulated by agents suchas LPS and zymosan. Overall, because myeloid and plasma-cytoid dendritic cells are isolated directly from the body,the profiling studies using these cells should be more rele-vant in understanding the role of dendritic cells in vivo than

in using dendritic cells differentiated in vitro from precursorcells.

One other class of dendritic cells that are being studied inprofiling experiments is dendritic cells that reside in tissue.One example of such cells are Langerhans cells of the skin,which are important in being amongst the primary cellswhich are first exposed to foreign antigen [2]. Profiling

experiments on these cell types are hampered by the difficul-ty to isolate them. However, in vitro models of differentiatingthese cells from CD34+ stem cells have been developed forLangerhans cells [46]. These models have been utilized ascell sources for profiling studies to understand their relation-ship to other types of dendritic cells [26].

Discoveries made from profiling studies of dendritic cells

There are a number of different objectives that could beachieved with profiling experiments in general and in partic-ular with dendritic cells. First would be the identification of

molecules involved in pathways that are known to be impor-tant in dendritic cell function. These could be molecules thatare already known based on previous studies, for example theexpression of the mannose receptor in immature dendriticcells or the expression of CD86 in mature dendritic cells, ornovel molecules. Secondly, there would be the identificationof pathways that may be overlooked, but serve an importantfunction in immature dendritic cell function. For example,molecules involved in cytoskeletal reorganization for vesicu-lar movements in immature dendritic cells. A third objectivewould be to obtain a broader understanding of dendritic cellfunction and its affects on other cell types. An example ofthis would be the identification of chemokines produced bydendritic cells that attract cell types not commonly associat-

ed with dendritic cells. Fourth would be the identification ofnovel molecules in dendritic cells that regulate dendritic cellfunction. A good example of this is GPR105 that was identi-fied on immature dendritic cells and whose ligand, UDP glu-cose, was found to mature dendritic cells [31]. Lastly, is theidentification of novel pathways that exist in dendritic cells.

Although a large number of genes have been identified in profiling studies to be expressed in immature or maturehuman monocyte derived dendritic cells, the one caveat tothese studies is that most of the genes identified have notbeen confirmed to be regulated by some more quantitativemeans, such as by northern analysis or quantitative PCR.Among the genes identified by profiling experiments that

have been confirmed to be expressed in immature dendriticcells include antigen uptake receptors (mannose receptor[19]), antigen presentation molecules (CD1e [10]), cell sig-naling molecules (alpha catenin [14], AS1 protein [15]),chemokines (MCP-4 [7, 10, 19], CCL15 [31], CCL23 [31],TARC [7, 19]), cytoskeleton associated molecules (AP-50[10], dihydropyrimidinase related protein 2 [10], gelsolin[10], arp2/3 protein complex subunit p16-Arc [15], clathrinassociated protein [15]), cytokines (TNF- [14]), ion chan-nels/transporters (MRP-4 [10], voltage dependent anionchannel [15]), metabolism associated molecules (inosinicase[7], cytochrome b561 [10], phosphofructokinase [7,15], coreI protein [15], fatty acid synthetase [15], lipase A[19]), pro-teases and protease inhibitors (hepatocyte growth factor acti-



6/18

vator inhibitor [7], cathepsin C [7], metalloproteinase [7],kunitz-type protease inhibitor [15], CD26 [10]), receptors(CD32 [10], TNFR II [14], CCR1 [31], CCR5 [31], GPR105[31]), transcription factors (aconitase [15]), and other mis-cellaneous proteins (CD63 [10], motor protein [15], highdensity lipoprotein binding protein [15], osteopontin[19],GPNMB [19]). As similar set of genes initially found by pro-

filing have been confirmed to be expressed in mature den-dritic cells such as apoptosis-associated molecules (NAIP[22], IAP-B [32], IAP-C [22, 32]) cell signaling molecules(DAPP-1 [32]), chemokines (MDC [12], MIG [12], CCL18[26], TARC [31, 32], MIP-1a [32], MIP-1b [32], MIP-2a[32], MIP2b [32], IL-8 [32], MGSA [32], MIP-1d [32],RANTES [32], TARC [32],) cytokines (IL-12p40 [9, 12], IL-12p35 [9], EBI3 [9]), cytoskeleton associated molecules(actin-bundling protein [9], kinesin-2 [32]), metabolismassociated molecules (MT2A [32]), proteases and proteaseinhibitors (cystatin F [9], PSMA3 [22]), receptors (CCR7 [9,31]), T cell activation molecules (SLAM [12]), transcriptionfactors (TFEC [22], IRF-1 [32], IRF-4 [32]), and other mis-

cellaneous molecules (HEM45 [9], DC-LAMP [9], IFNinducible protein p27 [9], TrpTS [22], CD63 [22], clusterin[32]).

Another approach to discern what genes identified byprofiling studies are truly differentially expressed in humanmonocyte derived dendritic cells, either immature or maturedwith a respective agent, would be assume that such geneswould be identified in multiple independent studies. Wetherefore compared the results from various profiling studiesto identify genes or proteins that were found to be differen-tially expressed in more than one independent study for thesame condition (immature dendritic cell [7, 10, 14, 1719,28]-Table 2; dendritic cells matured with LPS [9, 13, 29]-Table 3; dendritic cells matured with TNF- [8, 1619, 21,

28]-Table 4; and dendritic cells matured with CD40L [12, 18,32]-Table 5). Because of the different names, GenBankaccession numbers, etc. used by the different publications todenote their gene of interest, we decided to use LocusLink[47] abbreviations and identification numbers in the tables asa method to unify the various definitions. We also gave abrief summary of the protein coding for the gene, based oninformation obtained from Locus Link [47] or OnlineMendelian Inheritance in Man (OMIM) [48].

In such an analysis for immature dendritic cells, therewere a number of genes identif ied (Table 2) which were con-firmed to be regulated in other studies, such as CD1e, MCP-4, TARC, and TNF-. In addition, there were a number of

genes expressed in immature dendritic cells which were forparticular protein families. For example, a number of genesfor proteins involved in lipid transport were found to bereproducibly upregulated when monocytes were differentiat-ed to dendritic cells. These molecules, along with the find-ings of the upregulation of genes for different CD1 subfami-ly molecules and lipid metabolizing molecules, implies theimportant role non-peptide antigen presentation may havewith dendritic cells. Indeed, CD1 mediated lipid presentationand activation of T cells has been speculated to be an earlyand efficient adaptive immune response [49]. In addition, ithas been shown that interaction of dendritic cells with CD1restrictive T cells can be an important influence in the regu-lation of dendritic cell cytokine production and thereby mod-

ulating the ability of dendritic cells to differentiate T helpercells [50, 51]. Overall, both the profiling data and the litera-ture data tend to complement each other to support a relevantrole for lipid presentation in dendritic cell biology.

For dendritic cells matured with agents such as LPS,TNF-, or CD40L; this analysis revealed, despite the differ-ences in signaling induced by the different stimuli, a com-

mon pattern of regulation. Thus LPS and TNF- induced asignificant number of genes for various chemokines andtranscription factors. The induction of chemokine genes indi-cates a role of dendritic cells for attracting different immuno-cytes to the site of inflammation. The production of T cellattractant chemokines has been reported previously [52] andis not surprising considering their role in T cell activation.However, the upregulation of neutrophil chemoattractantsimplies a potential role of dendritic cells in neutrophil func-tion or visa versa. This prospective relationship betweendendritic cells and neutrophils has not been commonly sug-gested. Recently it has been reported that activated neu-trophils stimulate dendritic cells maturation and cytokine

production [53]. However, very little else has been publishedand thus this area may be of potential value, at least based onthe profiling studies.

The induction of genes for transcription factors indicatesthat dendritic cell maturation involves a complex set of regu-latory events with multiple transcription factors beinginvolved. This regulation of genes for transcription factorsinclude transcription factors commonly associated with LPSand TNF- signaling, such as NFB components and IRFtranscription factors, and additional transcription factors notcommonly associated with their signaling, such as STATmolecules.

As indicated above, one of the more exciting areas of den-dritic cell research is the recent profiling of dendritic cells

isolated from blood. Although a limited number of studieshave been done [19, 23], some genes have been identified by profiling that have been verified by other means, such asCD62L, CD123, CXCR4, Eph-B1, spi-B transcription fac-tor, ILT7, and a number of novel molecules [23]. One of these proteins, spi-B, was further shown, by overexpressing theprotein in hematopoietic progenitor cells, to be involved inplasmacytoid dendritic cell development [54].

Although it is interesting to speculate on the role thesemolecules have in dendritic cell function, experimentsaddressing their specific functions in dendritic cell biologyare limited. For cell surface molecules, activating or inhibito-ry antibodies could be used to discern the function of such

molecules on dendritic cells. An example of such work is inthe case of the identification of SLAM expression on maturedendritic cells [12]. In these studies, the authors found thatstimulatory antibodies to SLAM enhanced the expression ofproinflammatory cytokines from dendritic cells [12]. In caseswhere the ligand is known for the receptor, the role a receptorhas with dendritic cells could be discerned, as described abovefor GPR105 using its ligand UDP-glucose [31].

However, for most other molecules, the only way that thefunction of a given molecule could be determined would beto genetically modulate the expression or the function of theprotein in the dendritic cell. To do this, the gene, expressingthe wild-type protein or a dominant negative form of the pro-tein would need to be introduced into dendritic cells. A num-



7/18


Table 2. Upregulated genes identified in multiple profiling studies following differentiation of monocytes to dendritic cells.

Locus Link Name Locus Link ID Additional names Description

Antigen presentation/processingCD1a 909 glycolipid presentation

CD1c 911 glycolipid presentation

CD1e 913 membrane protein involved in the presentation of glycolipids

CD74 972 HLA-DR-gamma, MHC class II antigen presentationinvariant gamma chain

HLA-DPA1 3113 MHC class II DP alpha 1, antigen presentationHLA-SB alpha

HLA-DRA 3122 major histocompatibility HLA class II subunit involved in antigen presentationcomplex, class II, DR alphaprecursor

Cell signalingCTNNA1 1495 alpha catenin associated with signal induction via cell adhesion

DUSP1 1843 dual-specif icity phosphatase 1 serine/threonine phosphatase which can inactivate MAP kinase

GNAI2 2771 guanine nucleotide binding G-protein alpha subunitprotein (G protein), alphainhibiting activity polypeptide 2

GUK1 2987 guanylate kinase 1 enzyme which phosphorylates GMP to GDP

LYN 4067 v-yes-1, Yamaguchi sarcoma tyrosine kinase involved in receptor signal transductionviral related oncogene homolog

SLA 6503 SLAP, Src-like adapter protein adapter protein involved in receptor signaling

Cell survival/apoptosis/proliferationGAS6 2621 growth arrest-specif ic protein 6, protein thought to be involved in cell proliferation

AXL stimulatory factor

SEMA3C 10512 semaphorin E secreted protein associated with cell survival and morphogenesis

ChemokinesCCL5 6352 RANTES, SCYA5 chemoattractant for memory T cells, monocytes, and eosinophilsCCL13 6357 MCP-4,SCYA-13 chemoattractant for basophils, T cells, monocytes, and eosinophilsCCL17 6361 TARC, SCYA17 T cell chemoattractantCCL18 6362 PARC, MIP-4, SCYA18 T cell chemoattractant

CCL22 6367 MDC, SCYA22, STCP-1 NK cell, activated T cell, and dendritic cell chemoattractant

Cytokines/hormonesCSF1 1435 colony stimulating macrophage cytokine

factor 1, MCSF

IL1B 3553 interleukin 1, beta inflammatory cytokine

IL1RN 3557 interleukin 1 receptor antagonist for interleukin 1 receptor antagonist, IL1RA

TGFB1 7040 transforming growth growth factor factor beta 1

TNF 7124 TNFa, tumor necrosis proinflammatory cytokinefactor alpha

Lipid transportAPOC1 341 apolipoprotein C-I involved in lipid transport

APOE 348 apolipoprotein E protein involved in the transport of cholesterol and other lipids

FABP4 2167 fatty acid binding protein 4 intracellular protein involved in fatty acid uptake,transport, and metabolism

FABP5 2171 fatty acid binding protein 5 intracellular protein involved in fatty acid uptake,transport, and metabolism

Lysosome functionLIPA 3988 lysosomal acid lipase, lipase A, lysosomal enzyme involved in the hydrolysis of cholesteryl

esters and triglycerides

LAMP3 27074 LAMP, DC-LAMP, lysosomal- lysosomal functionassociated membrane protein 3


8/18




Membrane proteinCD36 948 FAT, collagen type I receptor scavenger receptor for oxidized LDL, cell adhesion

CD44 960 H-CAM, hermes cell adhesion

CD53 963 MOX44 cell surface glycoprotein which interacts with integrins

CD58 965 lymphocyte function-associated immunoglobulin receptor family member involved in cell adhesionantigen 3, LFA3

CD63 967 LAMP-3 cell surface glycoprotein which complexes with integrins

ITGAX 3687 CD11c, alpha x integrin, CR4, cell adhesionleukocyte surface antigen p150

ITGB2 3689 CD18; integrin, beta 2 cell adhesion

ITGB5 3693 integrin, beta 2 cell adhesion

MRC1 4360 mannose receptor C type 1, membrane receptor involved in endocytosismacrophage mannose receptor

SPN 6693 CD43, sialophorin cell adhesion, possibly role in T cell activation

Membrane receptorsFCER1 2208 CD23, FCeRII immunoglobulin (IgE) receptor

FCGR2A 2212 CD32; FcgRIIa receptor immunoglobulin (IgG) receptor FCGR23A 2214 CD16; FcgRIIIa receptor immunoglobulin (IgG) receptor

IFNGR1 3459 CD119. Interferon gamma receptor ligand binding chain of interferon gamma receptor

IFNGR2 3460 interferon gamma receptor 2 beta chain of interferon gamma receptor

IL4R 3566 CD124, interleukin 4 receptor, subunit for formation of high aff inity IL-4 and IL-13 receptorsalpha chain

MetabolismALOX15 246 arachidonate 15-lipoxygenase enzyme involved in the production of bioactive lipid molecules

CAT 847 Catalase antioxidant enzyme, converting H2O2 to H2O

GLUD1 2746 glutamate dehydrogenase 1 involved in the synthesis and catabolism of glutamate

ITPKB 3707 Inositol-trisphosphate 3-kinase B, IP3 kinase which phosphorylates inositol 1,4,5 triphosphate toinositol 1,3,4,5 P4

LPL 4023 lipoprotein lipase, LIPD functions as a triglyceride hydrolase and associated withreceptor-mediated lipoprotein uptake

MAOA 4128 Monoamine oxidase A mitochondrial protein which degrades amine neurotransmitterssuch as dopamine and serotonin

PCBD 5092 Pterin-4a-carbinolamine enzyme involved in phenylalanine hydroxylationdehydratase, PCD

MGLL 11343 monoglyceride lipase lipid metabolism

MiscellaneousA2M 2 a2-macroglobulin protease inhibitor, cytokine transporter

ECM1 1893 extracellular matrix protein 1 extracellular matrix protein

F13A1 2162 factor XIIIa, coagulation factor XIII, transglutaminase involved in the gamma-glutamyl-epsilon-a1 polypeptide lysine crosslinking of fibrin molecules for coagulation

SERPINB6 5269 protease inhibitor 6 serine protease inhibitor

RNASE1 6035 RNAse A, family 1 (pancreatic) secretory ribonucleaseSPP1 6696 osteopontin, OPN, BNSP extracellular matrix protein

KIAA0100 9703 function unknown

KIAA0193 9805 secernin 1 cytosolic protein involved in secretion

SPINT2 10653 placental bikunin, HAI2, hepatocyte serine protease inhibitor growth factor activator inhibitor type 2

DIPA 11007 Hepatitis delta antigen interacting modulates hepatitis virus delta replicationprotein A

KIAA0179 23076 function unknown


9/18




Nuclear proteins/replication/translationSNRPN 6638 small nuclear ribonucleoprotein pre-mRNA processing

polypeptide N

HMGN3 9324 TRIP7 modulates chromatin structure to enhance transcriptional activity

BRRN1 23397 KIAA0074, barren homolog DNA replication(drosophila), HCAP-H

Protein chaperoneHSPB1 3315 HSP27, HSP28, hsp25, heat shock stress response protein

27 protein 1

Secreted proteases/cell migrationADAM8 101 CD156 cell surface metalloproteinaseC1QB 713 complement C1q B chain component of serum complement systemMMP12 4321 macrophage metalloelastase, HME extracellular matrix degradation

T cell activationCD86 942 CD28 antigen ligand 2, B7-2 immunoglobulin superfamily member which is a costimulatory

molecule for T cell activation

CD83 9308 immunoglobulin superfamily member important in dendritic

cell activation of T cellsTranscription factorAES 166 amino-terminal enhancer of split transcription co-repressor CEBPA 1050 CEBP transcription factor CITED2 10370 MRG1 Cbp/p300-interacting transcription transactivator

Vesicular movement/cytoskeleton reorganizationARHA 387 ras homolog gene family, member A; GTPase involved in cytoskeletal reorganization

RHOA

IGF2R 3482 CD222, IGF-2 receptor, insulin-like involved in sorting lysosomal enzymes to lysosomesgrowth factor receptor 2

VIM 7431 vimentin intermediate filament protein

VAMP8 8673 vesicle-associated membrane protein 8 membrane protein involved in vesicle traff icking(endobrevin)

TMSB10 9168 thymosin beta-10 involved in actin filament assemblyARPC2 10109 actin related protein 2/3 complex, subunit of arp2/3 complex which is involved in actin

subunit 2, 34 kDa; ARC34 polymerization

Table 3. Upregulated genes identified in multiple profiling .studies in dendritic cells upon LPS treatment.


Antigen presentation/processingHLA-A 3105 major histocompatability complex, MHC I component

class I, A

PSMA3 5684 proteasome (prosome, macropain) proteasome subunit, member of peptidase T1A familysubunit, alpha type, 3; HC8

PSMB8 5696 proteasome subunit, beta type 8; proteasome componentRING10; LMP7

PSMB10 5699 proteasome subunit, beta type, 10 proteasome subunit

PSME1 5720 proteasome (prosome, macropain) proteasome subunitactivator subunit 1 (PA28 alpha)

TAP1 6890 transporter 1, ATP-binding cassette, transporter involved in transporting peptides across ERsub-family B (MDR/TAP), RING4 for MHC I peptide loading

Cell signalingDUSP1 1843 dual-specif icity phosphatase 1 serine/threonine phosphatase which can inactivate MAP kinase



LYN 4067 v-yes-1 Yamaguchi sarcoma viral tyrosine kinase associated with receptor signaling,related oncogene homolog such as immunoglobulin receptors


10/18




RGS1 5996 regulator of G-protein signaling 1, IER1 negative regulator of G-protein coupled receptor signaling

TRAF1 7185 TNF receptor-associated factor 1 mediates signal transduction from TNF receptor superfamily members

TANK 10010 I-TRAF sequester and inhibitor of TRAF function

TNIP1 10318 NAF1, TNFAIP3 interacting protein which attenuates NFkB and ERK2 signalingprotein 1, ABIN-1

Cell survival/apoptosis/proliferationBIRC3 330 MIHC, CIAP2, AIP1 inhibitor of apoptosis

BCL2A1 597 BCL2-related protein A1 anti-apoptotic protein

CASP7 840 caspase 7, MHC3 cysteine protease which induces apoptosis

GADD45A 1647 growth arrest and DNA-damage- stress induced protein involved in growth suppressioninducible, alpha; DDIT1, GADD45

MCL1 4170 myeloid cell leukemia sequence 1 BCL-2 family member which is both anti- and pro- apoptoticdepending on isoform produced

BTG2 7832 B-cell translocation gene 2, PC3, TIS21 protein involved in regulation of G1/S transition in cell cycle

TAX1BP1 8887 Tax1 binding protein, T6BP, TXBP151 antiapoptotic protein

ChemokinesCXCL1 2919 GRO1, GRO alpha, SCYB1 neutrophil chemoattractantCXCL2 2920 GRO2, GRO beta, MIP2, SCYB2 neutrophil chemoattractantCXCL3 2921 GRO3, GRO gamma, MIP2B, SCYB3 neutrophil chemoattractantIL8 3576 interleukin 8, SCYB8 neutrophil and T cell chemoattractantCXCL9 4283 MIG, HUMIG, SCYB9 T cell chemoattractantCCL4 6351 MIP1B, LAG1, SCYA4 immunocyte chemoattractantCCL5 6352 RANTES, SCYA5 chemoattractant for memory T cells, monocytes, and eosinophilsCCL8 6355 MCP2, SCYA8, SCYA10 immunocyte chemoattractantCCL17 6361 TARC, SCYA17 T cell chemoattractantCCL19 6363 ELC, MIP3b, SCYA19 B cell, T cell, and dendritic cell chemoattractantCCL22 6367 MDC, SCYA22, STCP-1 NK cell, activated T cell, and dendritic cell chemoattractantCXCL11 6373 ITAC, IP9, SCYB11, SCYB9B T cell chemoattractant

Cytokines/hormonesIGFBP4 3487 insulin-like growth factor binding protein which interacts with insulin like growth factor

protein 4; IBP4IL1B 3553 interleukin 1, beta inflammatory cytokine

IL1RN 3557 interleukin 1 receptor antagonist, IL1RA antagonist for interleukin 1 receptor

IL6 3569 interleukin 6; interferon, beta 2 inflammatory cytokine

INHBA 3624 inhibin, beta A; RDF, FRP hormone and growth/differentiation factor

TGFA 7039 transforming growth factor, alpha inflammatory cytokine

PBEF 10135 pre-B-cell colony-enhancing factor B cell cytokine

Membrane proteinCD33 945 p67, SIGLEC-3 sialic acid recognizing cell surface lectin

SLC31A2 1318 solute carrier family 31 (copper copper transporter transporters), member 2; CTR2

ICAM1 3383 CD54 adhesion molecule

MRC1 4360 mannose receptor C type 1, membrane receptor involved in endocytosismacrophage mannose receptor

NINJ1 4814 ninjurin 1 adhesion molecule

Membrane receptorsADORA3 140 adenosine A3 receptor G-protein coupled receptor

CD97 976 TM7LN1 seven transmembrane protein with EGF-like modules thatbinds to CD55 (decay accelerating factor)

CCR7 1236 EBI1, chemokine receptor 7 chemokine receptor which binds CCL19


IL7R 3575 interleukin 7receptor cytokine receptor


11/18




IL13RA1 3597 interleukin receptor 13, alpha 1 primary binding subunit of IL13 receptor and possibly aIL4 receptor subunit

IL15RA 3601 Interleukin 15 receptor, alpha cytokine receptor

LY64 4064 lymphocyte antigen-64, CD180; RP105 pathogen receptor with structural similarities to Toll-like receptor 4

PTGER4 5734 prostaglandin E receptor 4, EP4 G-protein coupled receptor

CXCR4 7852 NPY3R, fusin, neuropeptide Y chemokine receptor for SDF-1receptor Y3

TNFSF10 8743 APO2L, TRAIL TNF ligand superfamily member which induces cell apoptosis

CCRL2 9034 CRAM-A, CRAM-B, CKRX chemokine receptor

MetabolismGK 2710 glycerol kinase enzyme involved in glycerol metabolism

INDO 3620 indoleamine-pyrrole 2,3 enzyme which catalyzes the degradation of L-tryptophandioxygenase; IDO to N-formylkynurenine

LDHA 3939 lactate dehydrogenase A, LDH1 glycolysis enzyme involved in the conversion of L-lactateand NAD to pyruvate and NADH

MT1E 4493 metallothionein 1E protein which binds heavy metals

MT1G 4495 metallothionein 1G protein which binds heavy metalsMT1H 4496 metallothionein 1H protein which binds heavy metals

MT1X 4501 metallothionein 1X protein which binds heavy metals

MT2A 4502 metallothionein 2A protein which binds heavy metals

NCF1 4687 neutrophil cytosolic factor 1, subunit of NADPH oxidaseNOXO2, p47phox

OAS2 4939 2-5-oligoadenylate synthetase catalyzes the 2,5 oligomers of adenosine to activate RNase L2, 69/71kDa

PGK1 5230 phosphoglycerate kinase 1 glycolysis enzyme catalyzing 1,3-diphosphoglycerate to3-phosphoglycerate

SAT 6303 spermidine/spermine N1- rate limiting enzyme in the catabolic pathway of acetyltransferase polyamine metabolism

SOD2 6648 superoxide dismutase 2, mitochondrial manganese superoxide dismutase

TXN 7295 thioredoxin oxidoreductase enzymeYWHAQ 10971 tyrosine 3/tryptophan 5-monooxygenase potentially associated with regulation of monoamine biosynthesis

activation protein, theta polypeptide;1C5; HS1; 14-3-3 protein tau

MiscellaneousBST2 684 bone marrow stromal cell antigen 2 function unknown

BTG1 694 B-cell translocation protein 1 function unknown

IFI35 3430 interferon-induced protein 35, IFP35 function unknown

IFIT4 3437 interferon-induced protein with function unknowntetratricopeptide repeats 4, CIG-49

LGALS3BP 3959 lectin, galactoside-binding, soluble, binds macrophage-associated lectin, MAC-2, and galectin 1,3 binding protein; MAC-2-BP a beta-galactoside binding protein

LGALS9 3965 lectin, galactoside-binding, soluble, beta-galactoside binding protein implicated in modulating

9; galectin 9; ecalectin cell-cell and cell-matrix interactionsMX2 4600 myxovirus (influenza virus) member of dynamin family and large GTPase family which

resistance 2, MXB exists as a nuclear form and a cytoplasmic form

QSCN6 5768 quiescin Q6 function unknown

RCN1 5954 reticulocalbin calcium binding protein located in lumen of ER

S100A9 6280 S100 calcium-binding protein A9, member of S100 family of calcium binding proteinscalgranulin B, MIF, NIF, P14, CAGB,CFAG, CGLB, L1AG, MRP14

TNFAIP2 7127 tumor necrosis factor-alpha induced function unknownprotein 2, B94 protein

PHLDA2 7262 pleckstrin homology-like domain, function unknownfamily A, member 2, IPL, TSSC3


12/18




WNT5A 7474 wingless-type MMTV integration site secreted signaling protein involved in differentiationfamily, member 5A

GIP2 9636 interferon, alpha inducible protein ubiquitin homolog(clone IFI-15K), ISG15

MRF-1 10865 modulator recognition factor I function unknown

TIP-1 30851 Tax interaction protein 1 function unknown

Nuclear proteins/replication/translationMX1 4599 myxovirus (influenza virus) resist- nuclear member of dynamin family and large GTPase family

ance 1, interferon-inducible proteinp78

PPP1R7 5510 protein phosphatase 1, regulatory regulatory subunit of serine/threonine phosphatasesubunit 7; SDS22 potentially involved in mitosis

WARS 7453 tryptophanyl tRNA synthetase enzyme which catalyzes the aminoacylation of tRNA (trp)with tryptophan

PTP4A1 7803 protein tyrosine phosphatase type IVA, tyrosine phosphatase which is a nuclear protein but may alsomember 1; PRL1 be associated with the plasma membrane

SUI1 10209 A121, ISO1 translation initiation factor

Protein chaperoneHSPA1A 3303 heat shock 70kDa protein 1A, molecular chaperone protein

HSP70-1A

HSPA4 3308 heat shock 70kDa protein 4, RY, molecular chaperone proteinAPG-2, hsp70

HSPB1 3315 heat shock 27kDa protein 1, HSP27, molecular chaperone proteinHSP28, Hsp25

Secreted proteases/cell migrationBF 629 B-factor, properdin, complement factor complement protein

B preproprotein

MMP1 4312 matrix metalloproteinase 1, secreted proteinase which digests interstitial collagens type I,interstitial collagenase II, and III

MMP9 4318 matrix metalloproteinase 9, gelatinase B secreted protease which degrades type IV and V collagen

MMP12 4321 macrophage metalloelastase, HME extracellular matrix degradationMMP19 4327 matrix metalloproteinase 19; MMP18; matrix metalloproteinase whose function is unknown

RASI-1

TNFAIP6 7130 tumor necrosis factor-alpha induced secretory protein with hyaluronan-binding domain, a domainprotein 6, TSG6 associated with extracellular matrix stability and cell migration

T cell activationCD86 942 CD28 antigen ligand 2, B7-2 immunoglobulin superfamily member which is a costimulatory

molecule for T cell activation

SLAMF1 6504 SLAM, CDw150 immunoglobulin superfamily member involved in T cell andB cell stimulation

CD83 9308 immunoglobulin superfamily member important in dendriticcell activation of T cells

Transcription factor

RUNX3 864 runt-related transcription factor 3, transcription factor AML2, CBFA3

IRF1 3659 interferon regulatory factor 1, MAR transcription factor which activates interferons alpha andbeta transcription

IRF2 3660 interferon regulatory factor 2 competitively inhibits IRF1 mediated activation of interferonsalpha and beta transcription

IRF4 3662 interferon regulatory factor 4, MUM1 transcription factor involved in B cell development

IRF7 3665 interferon regulatory factor 7 transcription factor which activates interferon beta transcription

LYL1 4066 lymphoblastic leukemia derived Potentially involved in transcriptional regulationsequence 1

NFE2L2 4780 nuclear factor (erythroid-derived 2)- transcription factor involved in antioxidant responselike 2, NRF2


13/18




NFKB2 4791 nuclear factor of kappa light poly- transcription factor NfkB subunitpeptide gene enhancer in B-cells 2(p49/p100), LYT10

NFKBIA 4792 MAD-3, IKBA, I kappa B alpha inhibitory subunit of NFkB

STAT1 6772 signal transducer and activator of transcription factor phosphorylated and activated in cells intranscription 1 response to cytokines and growth factors

STAT4 6775 signal transducer and activator of transcription factor phosphorylated and activated in cells intranscription 4 response to cytokines and growth factors

STAT5A 6776 signal transducer and activator of transcription factor phosphorylated and activated in cells intranscription 5A response to cytokines and growth factors

VDR 7421 vitamin D (1,25-dihydroxyvitamin steroid hormone receptor superfamily member D3) receptor

NMI 9111 N-myc and STAT interactor augments STAT mediated transcription

ISGF3G 10379 interferon-stimulated transcription transcription factor which stimulates transcription of interferonfactor 3, gamma (48kD); p48; alpha inducible genesIRF9; ISGF3

PNRC1 10957 PROL2, B4-2, PRR2 nuclear receptor coactivator

Vesicular movement/cytoskeleton reorganizationDAB2 1601 disabled homolog 2, mitogen- protein potentially involved in exocytosis

responsive phosphoprotein(Drosophila); DOC2

PLEK 5341 pleckstrin, p47 protein kinase C substrate associated with phagosomal membranes

FSCN1 6624 SNL, fascin homolog 1, fascin 1 putative actin bundling factor

TRIP10 9322 thyroid hormone receptor interactor 10 possible regulation of actin cytoskeleton

CKAP4 10970 cytoskeleton-associated protein 4, microtubule binding protein located in the endoplasmic reticulump63, CLIMP-63

MLP 65108 macmarcks, MARCKS-like protein protein kinase C substrate potentially involved in cytoskeletalorganization

Table 4. Upregulated genes identified in multiple profiling .studies in dendritic cells upon TNF-atreatment.


Antigen presentation/processingPSME2 5721 proteasome activator subunit 2, proteasome subunit

PA28beta

TAP1 6890 transporter 1, ATP-binding cassette, transporter involved in transporting peptides across ER for sub-family B (MDR/TAP), RING4 MHC I peptide loading

Cell signalingDUSP4 1846 dual specif icity phosphatase 4, TYP, serine/threonine phosphatase which can inactivate MAP kinase

HVH2, MKP2, MKP-2

PRKAR2B 5577 protein kinase, cAMP-dependent, regulatory subunit for cAMP dependent protein kinase

regulatory, type II, beta; PRKAR2;RII-BETA

TRAF1 7185 TNF receptor-associated factor 1 mediates signal transduction from TNF receptor superfamilymembers

Cell survival/apoptosis/proliferationBIRC3 330 MIHC, CIAP2, AIP1 inhibitor of apoptosis

MCM5 4174 minichromosome maintenance def icient protein potentially involved in cell cycle regulationprotein 5, CDC46 homolog, CDC46

STK4 6789 KRS2, MST1 serine/threonine kinase associated with apoptosis

ChemokinesIL8 3576 interleukin 8, SCYB8 neutrophil and T cell chemoattractant

CCL2 6347 HC11, MCAF, MCP1, MCP-1, SCYA2, immunocyte chemoattractantGDCF-2


14/18




CCL5 6352 RANTES, SCYA5 chemoattractant for memory T cells, monocytes, and eosinophils

CCL8 6355 MCP2, SCYA8, SCYA10 immunocyte chemoattractant

CCL17 6361 TARC, SCYA17 T cell chemoattractant

Cytokines/hormonesIL6 3569 interleukin 6; interferon, beta 2 inflammatory cytokineTGFA 7039 transforming growth factor, alpha inflammatory cytokine

Lysosome functionLAMP3 27074 LAMP, DC-LAMP, lysosomal- lysosomal function

associated membrane protein 3

Membrane proteinCD44 960 H-CAM, hermes cell adhesion

ICAM1 3383 CD54 adhesion molecule

PLAUR 5329 plasminogen activator, urokinase membrane protein involved in cell surface plasminogenreceptor; CD87; UPAR; URKR activation; potential role in cell adhesion

SLC3A2 6520 solute car rier family 3, member 2; neutral and positive charged amino acid transporter 4F2; CD98; MDU1; 4F2HC; NACAE

PSCDBP 9595 pleckstrin homology, Sec7 and coiled- potential involvement in cell adhesioncoil domains, binding protein; HE;B3-1; CYBR

Membrane receptorsCD58 965 lymphocyte function-associated immunoglobulin receptor family member involved in cell adhesion

antigen 3, LFA3

CCR7 1236 EBI1, chemokine receptor 7 chemokine receptor which binds CCL19

FLT3 2322 fms-related tyrosine kinase 3, FLK2, growth factor receptor tyrosine kinase family member STK1, CD135

IGF1R 3480 insulin-like growth factor 1 receptor growth factor receptor tyrosine kinase family member


IL7R 3575 interleukin 7receptor cytokine receptor

IL15RA 3601 Interleukin 15 receptor, alpha cytokine receptor TM7SF1 7107 transmembrane 7 superfamily G-protein coupled receptor

member 1 (upregulated in kidney)

CXCR4 7852 NPY3R, fusin, neuropeptide Y chemokine receptor for SDF-1receptor Y3

TNFRSF11A 8792 tumor necrosis factor receptor super- TNF receptor superfamily member family, member 11a, EOF, PDB2, RANK

MetabolismALOX15B 247 arachidonate 15-lipoxygenase, enzyme which catalyzes the oxygenation of arachidonic acid

second type at the 15S position

INDO 3620 indoleamine-pyrrole 2,3 dioxygenase; enzyme which catalyzes the degradation of L-tryptophanIDO to N-formylkynurenine

PFKM 5312 phosphofructokinase, muscle glycolysis enzyme which converts fructose 6-phosphate tofructose 1,6-bisphosphate

SOD2 6648 superoxide dismutase 2, mitochondrial manganese superoxide dismutase

MGLL 11343 monoglyceride lipase lipid metabolism

MiscellaneousBTG1 694 B-cell translocation protein 1 function unknown

GRSF1 2926 G-rich RNA sequence binding factor 1 cellular protein which binds RNAs containing the G-rich element

LGALS9 3965 lectin, galactoside-binding, soluble, 9; beta-galactoside binding protein implicated in modulatinggalectin 9; ecalectin cell-cell and cell-matrix interactions

TGM2 7052 transglutaminase 2 (C polypeptide, enzyme involved in the crosslinking of proteins by epsilon-protein-glutamine-gamma-glutamyl- gamma glutamyl lysine isopeptide bondstransferase); TGC

TNFAIP2 7127 tumor necrosis factor-alpha induced function unknownprotein 2, B94 protein


15/18




TNFAIP6 7130 tumor necrosis factor-alpha induced secretory protein with hyaluronan-binding domain, a domainprotein 6, TSG6 associated with extracellular matrix stability and cell migration

OPTN 10133 optineurin, NRP, FIP2, HIP7, HYPL, protein which interacts with adenovirus E3 14.7K protein andGLC1E, TFIIIA-INTP transcription factor IIIA

FLN29 10906 function unknown

MMD 23531 monocyte to macrophage differen- function unknowntiation-associated, MMA

Nuclear proteins/replication/translationNBS1 4683 nibrin, p95 protein of the MRE11/ protein believed to be involved in DNA double-strand break

RAD50 complex, ATV, NBS, AT-V1, repair and DNA damage-induced checkpoint activationAT-V2

Protein chaperoneSIAH2 6478 seven in absentia homolog 2 regulator of protein stability

T cell activationSLAMF1 6504 SLAM, CDw150 immunoglobulin superfamily member involved in T cell and

B cell stimulation

CD83 9308 immunoglobulin superfamily member important in dendritic

cell activation of T cells

Transcription factorFOXO1A 2308 forkhead box O1A, FKH1, FKHR, transcription factor

FOXO1

ID2 3398 inhibitor of DNA binding 2, IDA2 transcriptional regulator

IRF4 3662 interferon regulatory factor 4, MUM1 transcription factor involved in B cell development

NFKBIA 4792 MAD-3, IKBA, I kappa B alpha inhibitory subunit of NF kB

NFKBIE 4794 nuclear factor of kappa light poly- inhibitory subunit of NF kBpeptide gene enhancer in B-cellsinhibitor, epsilon; IKBE

RELB 5791 nuclear factor of kappa light polypep- transcription factor Nf kB subunittide gene enhancer in B-cells 3, I-REL

REL 5966 transcription factor, component of NF-kB

STAT5A 6776 signal transducer and activator of transcription factor phosphorylated and activated in cellstranscription 5A in response to cytokines and growth factors

TNFAIP3 7128 tumor necrosis factor, alpha-induced zinc f inger protein which inhibits NfkB activation andprotein 3; A20; TNFA1P2 TNF induced apoptosis

NR4A3 8013 nuclear receptor subfamily 4, group A, steroid hormone receptor superfamily member member 3; CHN; TEC; CSMF; NOR1;MINOR

Vesicular movement/cytoskeleton reorganizationKIF2 3796 kinesin heavy chain member 2, HK2 microtubule associated motor protein

LAD1 3898 ladinin 1, LADA potential anchoring filament that is component of basement membranes

LAMB3 3914 laminin, beta 3; LAMNB1; subunit of laminin, a family of basement membrane proteins

MARCKS 4082 myristoylated alanine-rich protein actin f ilament crosslinking protein

kinase C substrate, phosphomyristin,MACS, PKCSL


16/18


ber of techniques using viral transduction methods have beenpublished to introduce genes into dendritic cells for valida-tion purposes, such as the introduction into dendritic cells ofdominant-negative forms of NFB inducing kinase and IBkinase 2 [55] and p27KIP1 [56].

There are potential issues with using the overexpressionof proteins to validate the role of the protein in dendriticcells. One caveat with the viral transduction methods isthat the effects the process itself has on the function of thedendritic cell needs to be closely monitored. Another issueis that overexpressing a protein or a dominant negative formof the protein may not be a feasible method for validating

the function of certain types of proteins, for example pro-teases. In these cases, a method for the knockdown of theexpression of a protein in a cell would be more appropriate.With the advent of siRNA technology, such an approachis beginning to be utilized in dendritic cells to reduce theexpression of a protein to determine its role in the cell[57, 58]. For example siRNA technology was used byLaderach et al. (2003) in showing the importance of the p50subunit of NF-B for the CD40L/IL-1 mediated inductionof IL-12 production in human monocyte derived dendriticcells [57]. Such approaches will become more significant inthe future as we go beyond the profiling experiments todetermine the role the identified genes have in dendritic cellfunction.

Conclusion

The accumulation of data being generated these past coupleof years from profiling the expression of proteins and genesin human dendritic cells have yielded a wealth of excitinginformation. However, a number of challenges need to befaced in the future. First, as our abilities to identify and iso-late dendritic cells produced in vivo improves; we need tofocus on profiling the genes and proteins expressed in thesecells. This capability will be also enhanced with the improve-ments of methods to perform profiling experiments with lessRNA, and subsequently less cells. Such studies are initiating

with profiling studies beginning to be published from in vivoproduced plasmacytoid cells and the preparation of Langer-hans cells differentiated in vitro. Although the informationgenerated using monocyte derived dendritic cells has greatlyincreased our understanding of dendritic cell biology, greaterrelevance will come from studying the cells that actuallyexist in vivo.

Secondly, as data from profiling experiments continues tobe generated, the next challenge will be to be able to effi-ciently utilize this information in experiments to determinethe role of the respective protein or pathway has in dendriticcell function. This will involve using techniques, such as ade-noviral transduction, to efficiently introduce genes into den-dritic cells to modulate the levels of the respective protein or

Table 5. Upregulated genes identified in multiple profiling .studies in dendritic cells upon CD40L treatment.


Antigen presentation/processingB2M 567 beta-2-microglobulin component of MHC1 complex

Cell survival/apoptosis/proliferationBIRC3 330 MIHC, CIAP2, AIP1 Inhibitor of apoptosisCCNG2 901 cyclin G2 regulation of cell cycle

ChemokinesIL8 3576 interleukin 8, SCYB8 neutrophil and T cell chemoattractantCXCL9 4283 MIG, HUMIG, SCYB9 T cell chemoattractantCCL17 6361 TARC, SCYA17 T cell chemoattractantCCL20 6364 MIP-3a, LARC, SCYA20 lymphocyte chemoattractant

Cytokines/hormonesIL1B 3553 interleukin 1, beta inflammatory cytokine

Membrane receptorsCCR7 1236 EBI1, chemokine receptor 7 chemokine receptor which binds CCL19

Protein chaperoneHSPCA 3320 heat shock 90kD protein 1, alpha; hsp90 molecular chaperone protein

T cell activationSLAMF1 6504 SLAM, CDw150 immunoglobulin superfamily member involved in T cell andB cell stimulation

CD83 9308 immunoglobulin superfamily member important in dendriticcell activation of T cells

Transcription factorIRF1 3659 interferon regulatory factor 1, MAR transcription factor which activates interferons alpha and

beta transcription

REL 5966 transcription factor, component of NF-kB

Vesicular movement/cytoskeleton reorganizationCHS1 1130 Chediak-Higashi syndrome 1, beige lysosomal trafficking regulator

protein, CHS


17/18

to introduce dominant negative forms of the protein to inhib-it its function. In addition, the advent of siRNA technologyestablishes a possibility to determine the role of proteins incells where overexpression or the use of dominant negativesare not feasible, such as in determining the role of proteasesin dendritic cell function.

In summary, a great deal of knowledge has been generat-

ed through profiling experiments that have increased ourunderstanding of the biology of dendritic cells. This infor-mation will only increase as more sophisticated methods areused to isolate rare types of dendritic cells for profilingexperiments. Such data presently existing and being generat-ed in the future will be form the basis of experiments touncover the role of particular proteins or pathways in thesecells.

References

[1] Banchereau J, Steinman RM. Dendritic cells and the control ofimmunity. Nature 1999; 392: 24552.

[2] Steinman RM. Dendritic cells. In: Paul WE, editor. FundamentalImmunology, Fourth Edition. Philadelphia:Lippincott-Raven,1999: 54773.

[3] Lambrecht BN, Hammad H. Taking our breath away: dendriticcells in the pathogenesis of asthma. Nat Rev Immunol 2003; 3:9941003.

[4] Pettit AR, Thomas R. Dendritic cells: the driving force behindautoimmunity in rheumatoid arthritis? Immunol Cell Biol 1999;77: 4207.

[5] Pascual V, Banchereau J, Palucka AK. The central role of dendrit-ic cells and interferon-alpha in SLE. Curr Opin Rheumatol 2003;15: 45856.

[6] Link H, Huang Y-M, Xiao B-G. Dendritic cells in experimentalallergic encephalomyelitis and multiple sclerosis. J Neuroim-munol 199; 100: 10210.

[7] Hashimoto S-I, Suzuki T, Dong H-Y, Nagai S, Yamazaki N, Mat-sushima K. Serial analysis of gene expression in human mono-cyte-derived dendritic cells. Blood 1999; 94: 84552.

[8] Dietz AB, Bulur PA, Knutson GJ, Matasic R, Vuc-Pavlovic S.Maturation of human monocyte-derived dendritic cells studied bymicroarray hybridization. Biochem Biophys Res Commun 2000;275: 7318.

[9] Hashimoto S-I, Suzuki T, Nagai S, Yamashita T, Toyoda N, Mat-sushima K. Identification of genes specifically expressed inhuman activated and mature dendritic cells through serial analysisof gene expression. Blood 2000; 96: 220614.

[10] Angnieux C, Fricker D, Strub J-M, Luche S, Bausinger H,Cazenave J-P, et al. Gene induction during differentiation ofhuman monocytes into dendritic cells: an integrated study at theRNA and protein levels. Funct Integr Genomics 2001; 1: 3239.

[11] Baltathakis J, Alcantara O, Boldt DH. Expression of different NF-

B pathway genes in dendritic cells (DCs) or macrophages assessedby gene expression profiling. J Cell Biochem 2001; 83: 28190.[12] Bleharski JR, Niazi KR, Sieling PA, Cheng G, Modlin, RL. Sig-

naling lymphocytic activation molecule is expressed on CD40 lig-and-activated dendritic cells and directly augments production ofinflammatory cytokines. J Immunol 2001; 167: 317481.

[13] Huang Q, Liu D, Majewski P, Schulte LC, Korn JM, Young RA, etal. The plasticity of dendritic cell responses to pathogens and theircomponents. Science 2001; 294: 8705.

[14] Lapteva N, Ando Y, Nieda M, Hohjoh H, Okai M, Kikuchi A, et al.Profiling of genes expressed in human monocytes and monocyte-derived dendritic cells using cDNA expression array. Br J Haema-tol 2001; 114: 1917.

[15] Lapteva N, Nieda M, Ando Y, Nicol A, Ide K, Yamaura A, et al.Gene expression analysis in human monocytes, monocyte-deriveddendritic cells, and a-galactosylceramide-pulsed monocyte-

derived dendritic cells. Biochem Biophys Res Commun 2001;289: 5318.

[16] Lapteva N, Nieda M, Ando Y, Ide K, Hatta-Ohashi Y, Dymshits G,et al. Expression of renin-angiotensin system genes in immatureand mature dendritic cells identif ied using human cDNA microar-ray. Biochem Biophys Res Commun 2001; 285: 105965.

[17] Le Naour F, Hohenkirk L, Grolleau A, Misek DE, Lescure P,Geiger JD, et al. Profiling changes in gene expression during dif-

ferentiation and maturation of monocyte-derived dendritic cellsusing both oligonucleotide microarrays and proteomics. Proc NatlAcad Sci USA 2001; 276: 1792031.

[18] Moschella F, Maffei A, Cantanzaro RP, Papadopoulos KP, SkerrettD, Hesdorffer CS, et al. Transcript profiling of human dendriticcells maturation-induced under defined culture conditions: comparison of the effects of tumour necrosis factor alpha, solubleCD40 ligand trimer and interferon gamma. Br J Haematol 2001;114: 44457.

[19] Ahn JH, Lee Y, Jeon CJ, Lee S-J, Lee B-H, Choi KD, et al. Identi-fication of the genes differentially expressed in human dendriticcell subsets by cDNA subtraction and microarray analysis. Blood2002; 100: 174254.

[20] Lapteva N, Ide K, Nieda M, Ando Y, Hatta-Ohashi Y, Minami M,et al. Activation and suppression of reonin-angiotensin system inhuman dendritic cells. Biochem Biophys Res Commun 2002; 296:

194200.[21] Lindstedt M., Johansson-Lindbom B, Borrebaeck CAK. Global

reprogramming of dendritic cells in response to a concerted actionof inflammatory mediators. Int Immunol 2002; 14: 120313.

[22] Matsunga T, Ishida T, Takekawa M, Nishimura S, Adachi M, ImaiK. Analysis of gene expression during maturation of immaturedendritic cells derived from peripheral blood monocytes. Scand JImmunol 2002; 56: 593601.

[23] Rissoan M-C, Duhen T, Bridon J-M, Vermare NB, Pronne C, VisBDS, et al. Subtractive hybridization reveals the expression ofimmunoglobulinlike transcript 7, Eph-B1, granzyme B, and 3 nov-el transcripts in human plasmacytoid dendritic cells. Blood 2002;100: 3295303.

[24] Schlaak JF, Hilkens CMU, Costa-Pereira AP, Strobl B, Aberger F,Frischauf A-M, et al. Cell-type and donor specific transcriptional

responses to interferon-. J Biol Chem 2002; 277: 4942837.[25] Chaussabel D, Semnani RT, McDowell MA, Sacks D, Sher A, Nut-man TB Unique gene expression profiles of human macrophagesand dendritic cells to phylogenetically distinct parasites. Blood2003; 102: 67281.

[26] Hashimoto S-I, Nagai S, Sese J, Suzuki T, Obata A, Sato T, et al.Gene expression profile in human leukocytes. Blood 2003; 101:350913.

[27] Izmailova E, Bertley FMN, Huang Q, Makori N, Miller CJ, YoungRA, et al. HIV-1 tat reprograms immature dendritic cells toexpress chemoattractants for activated T cells and macrophages.Nat Med 2003; 9: 1917.

[28] Ju X-S, Hacker C, Madruga J, Kurz SM, Knespel S, Blendinger G,et al. Towards determining the differentiation program of anti-gen presenting cells by transcriptional profiling. Eur J Cell Biol2003; 82: 7586.

[29] Messmer D, Messmer B, Chiorazzi N. The global transcriptionalmaturation program and stimuli-specific gene expression profilesof human myeloid dendritic cells. Int Immunol 2003; 15: 491503.

[30] Moschella F, Bisikirska B, Maffei A, Papadopoulos, KP, Skerrett,D, Liu Z, et al. Gene expression profiling and functional activityof human dendritic cells induced with IFN-a-2b: implications forcancer immunotherapy. Clin Cancer Res 2003; 9: 202231.

[31] Skelton L, Cooper M, Murphy M, Platt A. Human immaturemonocyte-derived dendritic cells express the G protein-coupledreceptor GPR105 (KIAA001, P2Y14) and increase intracellularcalcium in response to its agonist uridine diphosphoglucose. JImmunol 2003; 171: 19419.

[32] Treci O, Bian H, Nestle FO, Raddrizzani L, Rosinski JA, TassisA, et al. Cascades of transcriptional induction during dendritic cellmaturation revealed by genome-wide expression analysis. FASEBJ 2003; 17: 83647.



18/18

[46] Jaksits S, Kriehuber E, Charbonnier AS, Rappersberger K, StinglG, Maurer D. CD34+ cell-derived CD14+precursor cells developinto langerhans cells in a TGF-1-dependent manner. J Immunol1999; 163: 486977.

[47] http://www.ncbi.nlm.nih.gov/LocusLink/[48] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM[49] Vincent MS, Gumperz JE, Brenner MB. Understanding the func-

tion of CD1-restricted T cells. Nat Immunol 2003; 4: 51723.

[50] Vincent MS, Leslie DS, Gumperz JE, Xiong X, Grant EP, BrennerMB. CD1-dependent dendritic cell instruction. Nat Immunol2002; 3: 11638.

[51] Leslie DS, Vincent MS, Spada FM, Das H, Sugita M, Morita CT,et al. CD1-mediated / T cell maturation of dendritic cells. J ExpMed 2002; 196: 157584.

[52] Vissers JLM, Hartgers FC, Lindhout E, Teunissen MBM, FigdorCG, Adema GJ. Quantitative analysis of chemokine expression bydendritic cell subsets in vitro and in vivo. J Leukoc Biol 2001; 69:78593.

[53] Bennouna S, Bliss SK, Curiel TJ, Denkers EY. Cross-talk in theinnate immune system:neutrophils recruitment and activation ofdendritic cells during microbial infection. J Immunol 2003; 171:60528.

[54] Schotte R, Rissoan M-C, Vermare N-B, Bridon J-M, Dihen T, Wei-jer K, et al. The transcription factor Spi-B is expressed in plasma-

cytoid DC precursors and inhibits T-,B-, and NK-cell develop-ment. Blood 2003; 101: 101523.

[55] Andreakos E, Smith C, Monaco C, Brennan FM, Foxwell BM,Feldmann M. IB kinase 2 but not NF-B-inducing kinase is es-sential for efficient DC antigen presentation in the allogeneicmixed lymphocyte reaction. Blood 2003; 101: 98391.

[56] Woltman, AM, Van Der Kooij SW, Coffer PJ, Offringa R, DahaMR, Van Kooten C. Rapamycin specifically interferes with GM-CSF signaling in human dendritic cells, leading to apoptosis viaincreased p27CIP expression. Blood 2003; 101: 143945.

[57] Laderach D, Compagno D, Danos O, Vainchenker W, Galy A. RNAinterference shows critical requirement for NF-B p50 in the pro-duction of IL-12 by human dendritic cells. J Immunol 2003; 171:17507.

[58] Hill JA, Ichim TE, Kusznieruk KP, Li M, Huang X, Yan X, et al.

Immune modulation by silencing IL-12 production in dendri-tic cells using small interfering RNA. J Immunol 2003; 171:6916.


[33] Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and down-regulated by tumor necrosis factor. J Exp Med 1994; 179: 110918

[34] Bender A, Sapp M, Schuler G, Steinman RM, Bhardwaj N.Improved methods for the generation of dendritic cells from non- proliferating progenitors in human blood J Immunol Methods1996;196:121-135.

[35] Beutler B, Hoebe K, Du X, Ulevitch RJ. How we detect microbesand respond to them: Toll-like receptors and their transducers. JLeukoc Biol 2003; 74: 47985.

[36] Barton GM, Medzhitov R. Toll-like receptor signaling pathways.Science 2003; 300: 15245.

[37] Gaur U, Aggarwal BB. Regulation of proliferation, survival, andapoptosis by members of the TNF superfamily. Biochem Pharma-col 2003; 66: 14038.

[38] Lam N, Sudgen B. CD40L and its viral mimic, LMP1: similarmeans to different ends. Cell Signal 2002; 15: 916.

[39] Barton GM, Medzhitov R Linking Toll-like receptors to IFN-/expression. Nat Immunol 2003; 4: 4323.

[40] Agrawal S, Agrawal A, Doughty B, Gerwitz A, Blenis J, Van DykeT, et al. Different toll-like receptor agonists instruct dendritic cellsto induce distinct Th responses via differential modulation ofextracellular signal-regulated kinase-mitogen-activated protein

kinase and c-fos. J Immunol 2003; 171: 49849.[41] Kohrgruber N, Halanek N, Grger M, Winter D, Rappersberger K,

Schmitt-Egenolf M, et al. Survival, maturation, and function ofCD11c- and CD11c+peripheral blood dendritic cells are differen-tially regulated by cytokines. J Immunol 1999; 163: 32509.

[42] Brire F, Bendriss-Vermare N, Delale T, Burg S, Corbet C, RissoanM-C, et al. Origin and filiation of human plasmacytoid dendriticcells. Hum Immunol 2003; 63: 108192.

[43] Sigal FP, Kadowaki N, Shodell M, Fitzgerald-Bocarsly PA, ShahK, et al. The nature of the principal type 1 interferon-producingcells in human blood. Science 1999; 284: 18357.

[44] Kadowski N, Ho S, Antonenko S, Malefyt RDW, Kastelein RA,Bazan F, et al. Subsets of human dendritic cell precursors expressdifferent toll-like receptors and respond to different microbialantigens. J Exp Med 2001; 194: 8639.

[45] Jahnsen FL, Farkes L, Lund-Johansen F, Brandtzaeg P. Involve-ment of plasmacytoid dendritic cells in human disease. HumImmunol 2002; 63: 12015.

Dendritic Cell Gene Profile

Documents

Transcript of Dendritic Cell Gene Profile