Dendritic cells (DCs) play a key role in the interface between the innate and acquired immune systems. In response to both exogenous as well as endogenous signals, DCs undergo a programmed maturation to become an efficient, antigen-presenting cell. Yet little is known regarding the differential responses by endogenous versus exogenous stimuli on DC maturation. In the present report, we have compared the phenotypic, functional, and genome-wide expression responses associated with maturation by bone marrow derived DCs to either an endogenous danger signal, tumor necrosis factor-α (TNF-α), or a microbial product, bacterial lipopolysaccharide (LPS). Examination of the cell surface expression of DCs as well as cytokine production demonstrated that patterns of DC maturation varied dramatically depending upon the stimulus. Whereas LPS was highly effective in terms of inducing phenotypic and functional maturation, TNF-α exposure produced a phenotypically distinct DC. Gene expression patterns in DCs 6 and 24 h after LPS and TNF-α exposure revealed that these activation signals produce fundamentally different genomic responses. Supervised analysis revealed that the expression of 929 probe sets discriminated among the treatment groups, and the patterns of gene expression in TNF-α stimulated DCs were more similar to unstimulated cells at both 6 and 24 h post-stimulation than to LPS-stimulated cells at the same time points. These findings reveal that DCs are capable of a varying phenotypic response to different antigens and endogenous signals.
Steinman RM, Cohn ZAIdentification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J Exp Med1973; 137: 1142—1162.
2.
Steinman RM, Cohn ZAIdentification of a novel cell type in peripheral lymphoid organs of mice. II. Functional properties in vitro. J Exp Med1974; 139: 380—397.
3.
Steinman RM, Adams JC, Cohn ZAIdentification of a novel cell type in peripheral lymphoid organs of mice. IV. Identification and distribution in mouse spleen. J Exp Med1975; 141: 804—820.
4.
Rescigno M., Granucci F., Ricciardi-Castagnoli P.Dendritic cells at the end of the millennium. Immunol Cell Biol1999; 77: 404—410.
5.
Inaba K., Steinman RMProtein-specific helper T-lymphocyte formation initiated by dendritic cells . Science1985; 229: 475—479.
6.
Schuler G., Steinman RMMurine epidermal Langerhans cells mature into potent dendritic cells in vitro . J Exp Med1985; 161: 526—546.
7.
Inaba K., Schuler G., Witmer MD, Valinksy J., Atassi B., Steinman RMImmunologic properties of purified epidermal Langerhans cells. Distinct requirements for stimulation of unprimed and sensitized T lymphocytes. J Exp Med1986; 164: 605—613.
8.
Steinman RMDendritic cells and the control of immunity: enhancing the efficiency of antigen presentation. Mt Sinai J Med2001; 68: 106—166.
9.
Lipscomb MF, Masten BJDendritic cells: immune regulators in health and disease. Physiol Rev2002; 82: 97—130.
10.
Efron P., Moldawer LLSepsis and the dendritic cell. Shock2003; 20: 386—401.
11.
Zitvogel L.Dendritic and natural killer cells cooperate in the control/switch of innate immunity. J Exp Med2002; 195: F9—F14.
12.
Sporri R., Reis e Sousa C.Inflammatory mediators are insufficient for full dendritic cell activation and promote expansion of CD4+ T cell populations lacking helper function. Nat Immunol2005; 6: 163—170.
13.
Ebner S., Ratzinger G., Krosbacher B. et al. Production of IL-12 by human monocyte-derived dendritic cells is optimal when the stimulus is given at the onset of maturation, and is further enhanced by IL-4. J Immunol2001; 166: 633—641.
14.
Winzler C., Rovere P., Rescigno M. et al. Maturation stages of mouse dendritic cells in growth factor-dependent long-term cultures. J Exp Med1997; 185: 317—328.
15.
Buelens C., Verhasselt V., De Groote D., Thielemans K., Goldman M., Willems F.Human dendritic cell responses to lipopolysaccharide and CD40 ligation are differentially regulated by interleukin-10. Eur J Immunol1997; 27: 1848—1852.
16.
Fiebiger E. , Meraner P., Weber E. et al. Cytokines regulate proteolysis in major histocompatibility complex class IIdependent antigen presentation by dendritic cells. J Exp Med2001; 193: 881—892.
17.
Cella M., Engering A., Pinet V., Pieters J., Lanzavecchia A.Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells. Nature1997; 388: 782—787.
18.
Inaba K., Turley S., Iyoda T. et al. The formation of immunogenic major histocompatibility complex class II-peptide ligands in lysosomal compartments of dendritic cells is regulated by inflammatory stimuli. J Exp Med2000; 191: 927—936.
19.
Santambrogio L., Sato AK, Fischer FR, Dorf ME, Stern LJAbundant empty class II MHC molecules on the surface of immature dendritic cells. Proc Natl Acad Sci USA1999; 96: 15050—15055.
20.
Turley SJ, Inaba K., Garrett WS et al. Transport of peptide-MHC class II complexes in developing dendritic cells. Science2000; 288: 522—527.
21.
Weissman D. , Li Y., Orenstein JM, Fauci ASBoth a precursor and a mature population of dendritic cells can bind HIV. However, only the mature population that expresses CD80 can pass infection to unstimulated CD4+ T cells. J Immunol1995; 155: 4111—4117.
22.
Yoshimura S. , Bondeson J., Foxwell BM, Brennan FM, Feldmann M.Effective antigen presentation by dendritic cells is NF-kappaB dependent: coordinate regulation of MHC, co-stimulatory molecules and cytokines. Int Immunol2001; 13: 675—683.
23.
Inaba K., Inaba M., Romani N. et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med1992; 176: 1693—1702.
24.
Lutz MB, Kukutsch N., Ogilvie AL et al. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods1999; 223: 77—92.
25.
Feezor RJ, Oberholzer C., Baker HV et al. Molecular characterization of the acute inflammatory response to infections with Gram-negative versus Gram-positive bacteria. Infect Immun2003; 71: 5803—5813.
26.
Eisen MB, Spellman PT, Brown PO, Botstein D.Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA1998; 95: 14863—14868.
27.
Tusher VG, Tibshirani R., Chu G.Significance analysis of microarrays applied to the ionizing radiation response . Proc Natl Acad Sci USA2001; 98: 5116—5121.
28.
Huang Q., Liu D., Majewski P. et al. The plasticity of dendritic cell responses to pathogens and their components. Science2001; 294: 870—875.
29.
Inaba K., Witmer-Pack M., Inaba M. et al. The tissue distribution of the B7-2 costimulator in mice: abundant expression on dendritic cells in situ and during maturation in vitro. J Exp Med1994; 180: 1849—1860.
30.
Granucci F. , Vizzardelli C., Virzi E., Rescigno M., Ricciardi-Castagnoli P.Transcriptional reprogramming of dendritic cells by differentiation stimuli. Eur J Immunol2001; 31: 2539—2546.
31.
Moschella F. , Maffei A., Catanzaro RP et al. Transcript profiling of human dendritic cells maturation-induced under defined culture conditions: comparison of the effects of tumour necrosis factor alpha, soluble CD40 ligand trimer and interferon gamma. Br J Haematol2001; 114: 444—457.
32.
Tureci O., Bian H., Nestle FO et al. Cascades of transcriptional induction during dendritic cell maturation revealed by genome-wide expression analysis. FASEB J2003; 17: 836—847.
33.
Chen Z., Gordon JR, Zhang X., Xiang J.Analysis of the gene expression profiles of immature versus mature bone marrow-derived dendritic cells using DNA arrays. Biochem Biophys Res Commun2002; 290: 66—72.
34.
Langenkamp A., Messi M., Lanzavecchia A., Sallusto F.Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and non-polarized T cells. Nat Immunol2000; 1: 311—316.
35.
Caux C., Massacrier C., Vanbervliet B. et al. Activation of human dendritic cells through CD40 cross-linking . J Exp Med1994; 180: 1263—1272.
36.
Cella M., Scheidegger D., Palmer-Lehmann K., Lane P., Lanzavecchia A., Alber G.Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J Exp Med1996; 184: 747—752.
37.
Jonuleit H. , Kuhn U., Muller G. et al. Pro-inflammatory cytokines and prostaglandins induce maturation of potent immunostimulatory dendritic cells under fetal calf serum-free conditions. Eur J Immunol1997; 27: 3135—3142.
38.
Richards J. , Le Naour F, Hanash S., Beretta L.Integrated genomic and proteomic analysis of signaling pathways in dendritic cell differentiation and maturation. Ann NY Acad Sci2002; 975: 91—100.
39.
Lindstedt M. , Johansson-Lindbom B., Borrebaeck CAGlobal reprogramming of dendritic cells in response to a concerted action of inflammatory mediators . Int Immunol2002; 14: 1203—1213.
40.
Rescigno M. , Citterio S., Thery C. et al. Bacteria-induced neo-biosynthesis, stabilization, and surface expression of functional class I molecules in mouse dendritic cells. Proc Natl Acad Sci USA1998 ; 95: 5229—5234.
41.
Hashimoto SI , Suzuki T., Nagai S., Yamashita T., Toyoda N., Matsushima K.Identification of genes specifically expressed in human activated and mature dendritic cells through serial analysis of gene expression. Blood2000; 96: 2206—2214.
42.
Medzhitov R. , Preston-Hurlburt P., Janeway Jr CA. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity . Nature1997; 388: 394—397.
Oberholzer A., Oberholzer C., Moldawer LLSepsis syndromes: understanding the role of innate and acquired immunity. Shock2001; 16: 83—96.
45.
Gallucci S. , Lolkema M., Matzinger P.Natural adjuvants: endogenous activators of dendritic cells. Nat Med1999; 5: 1249—1255.
46.
Lanzavecchia A., Sallusto F.The instructive role of dendritic cells on T cell responses: lineages, plasticity and kinetics. Curr Opin Immunol2001; 13: 291—298.
47.
Takeuchi O. , Hoshino K., Kawai T. et al. Differential roles of TLR2 and TLR4 in recognition of Gram-negative and Gram-positive bacterial cell wall components . Immunity1999; 11: 443—451.
48.
Yoshimura A. , Lien E., Ingalls RR, Tuomanen E., Dziarski R., Golenbock D.Recognition of Gram-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2. J Immunol1999; 163: 1—5.
49.
Means TK, Wang S., Lien E., Yoshimura A., Golenbock DT, Fenton MJHuman Toll-like receptors mediate cellular activation by Mycobacterium tuberculosis . J Immunol1999; 163: 3920—3927.
50.
Kadowaki N. , Ho S., Antonenko S. et al. Subsets of human dendritic cell precursors express different Toll-like receptors and respond to different microbial antigens . J Exp Med2001; 194: 863—869.
51.
Dinarello CA, Moldawer LLProinflammatory and antiinflammatory cytokines in rheumatoid arthritis: a primer for clinicians. Thousand Oaks, CA: Amgen Inc., 2001.
52.
Sozzani S., Allavena P., D'Amico G. et al. Differential regulation of chemokine receptors during dendritic cell maturation: a model for their trafficking properties. J Immunol1998; 161: 1083—1086.
53.
Sallusto F. , Schaerli P., Loetscher P. et al. Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur J Immunol1998; 28: 2760—2769.
54.
Ku CC, Murakami M., Sakamoto A., Kappler J., Marrack P.Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science2000; 288: 675—678.
55.
Miller MD, Krangel MSBiology and biochemistry of the chemokines: a family of chemotactic and inflammatory cytokines. Crit Rev Immunol1992; 12: 17—46.
56.
Rollins BJChemokines. Blood1997; 90: 909—928.
57.
Baggiolini M.Chemokines and leukocyte traffic. Nature1998; 392: 565—568.
58.
Cyster JGChemokines and cell migration in secondary lymphoid organs. Science1999; 286: 2098—2102.
59.
Saeki H., Moore AM, Brown MJ, Hwang STSecondary lymphoid-tissue chemokine (SLC) and CC chemokine receptor 7 (CCR7) participate in the emigration pathway of mature dendritic cells from the skin to regional lymph nodes. J Immunol1999; 162: 2472—2475.
