Immunologic Research

, Volume 29, Issue 1–3, pp 187–196

Modulating Th1/Th2 responses with microbes, dendritic cells, and pathogen recognition receptors

  • Bali Pulendran
Immunology at Emory University


The adaptive immune system has evolved different types of immune responses, each one effective against a given class of pathogen. For example, Th1 and Th2 responses represent two qualitatively different types of immune responses that are preferentially effective against intracellular microbes and helminths, respectively. Since the original description of Th1 and Th2 T-cell clones (1), we have learned much about the cytokines that influence the type of Th response. Thus, interleukin-4 (IL-4) is known to induce IL-4 production in T cells; conversely IL-12 and interferon- γ (IFN-γ) are known to induce IFN-γ production by T cells. However, the original sources of these cytokines in vivo are less clear. Recent developments from several labs point to a potential role for dendritic cells (DCs) in orche strating this decision making process. Here, we present our current view of DC development, and then review the evidence for two opposing concepts: (1) that distinct subsets of DCs are predetermined to differentially bias the T-helper response; and (2) that microbes and the local microenvironment are potent modulators of DC function. Thus, nature appears to have evolved different mechanisms to regulate immune responses via DCs.

Key Words

Dendritic cells TLRs Th1/Th2 Innate immunity Adaptive immunity 


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  1. 1.
    Mosmann TR and Coffman RL: TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 1989;7: 145–173.PubMedCrossRefGoogle Scholar
  2. 2.
    Steinman RM and Cohn ZA: Identification of a novel cell type in peripheral lymphoid organs of mice. 1. Morphology, quantitation, tissue distribution. J Exp Med 1973;137:1142–1162.PubMedCrossRefGoogle Scholar
  3. 3.
    Banchereau J, Steinman RM: Dendritic cells and the control of immunity. Nature 1998;392:245–252.PubMedCrossRefGoogle Scholar
  4. 4.
    Shortman K, Liu, Y-J: Mouse and human dendritic cell subtypes. Nature Rev Immunol 2002;2:151–161.CrossRefGoogle Scholar
  5. 5.
    PulendranB, Maraskovsky E, Banchereau J et al.: Modulating the immune response with dendritic cells and their growth factors. Trends Immunol 2001;22: 41–47.PubMedCrossRefGoogle Scholar
  6. 6.
    Pulendran B, Smith JL, Caspary G et al.: Distinct dendritic cell subsets differentially regulate the class of immune response in vivo. Proc Natl Acad Sci U S A 1999;96:1036–1041.PubMedCrossRefGoogle Scholar
  7. 7.
    Maldonado-Lopez R, De Smedt T, Michel P. et al.: CD8alpha+ and CD8alpha− subclasses of dendritic cells direct the development of distinct T helper cells in vivo. J Exp Med 1999;189:587–592.PubMedCrossRefGoogle Scholar
  8. 8.
    Rissoan MC, Soumelis V, Kadowaki N et al.: Reciprocal control of T helper cell and dendritic cell differentiation. Science 1999;283:1183–1186.PubMedCrossRefGoogle Scholar
  9. 9.
    Pulendran B, Palucka K, Banchereau J: Sensing Pathogens and Tuning Immune Responses. Science 2001; 293:253–256.PubMedCrossRefGoogle Scholar
  10. 10.
    Lanzavecchia A, Sallusto F: Regulation of T-cell immunity by dendritic cells. Cell 2001;106:263–266.PubMedCrossRefGoogle Scholar
  11. 11.
    Kalinski P, Hilkens CM, Wierenga EA et al.: T-cell priming by type-1 and type-2 polarized dendritic cells: the concept of a third signal. Immunol Today 1999;20:561–567.PubMedCrossRefGoogle Scholar
  12. 12.
    Valladeau J, Ravel O, Dezutter-Dambuyant C et al.: Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules. Immunity 2000;12:71–81.PubMedCrossRefGoogle Scholar
  13. 13.
    Asselin-Paturel C, Boonstra A, Dalod M et al.: Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nature Immunol 2001;2:1144–1150.CrossRefGoogle Scholar
  14. 14.
    Nakano H., Yanagita, M., Gunn, M. D: CD11c+B220+ Gr-1+ cells in mouse lymph nodes and spleen display characteristics of plasmacytoid dendritic cells. J Exp Med 2001;194:1171–1178.PubMedCrossRefGoogle Scholar
  15. 15.
    Bjorck, P: Isolation and characterization of plasmacytoid dendritic cells from Flt3-Ligand and granulocyte-macrophage colony stimulating factor treated mice. Blood 2001;98:3520–3526.PubMedCrossRefGoogle Scholar
  16. 16.
    Grouard G, Rissoan MC, Filgueira L et al.: The enigmatic plasmacytoid T-cells develop into dendritic cells with interleukin-3 (IL)-3 and CD40-ligand. J Exp Med 1996;184:1101–1111.CrossRefGoogle Scholar
  17. 17.
    Siegal FP, Kadowaki N, Shodell M et al.: The nature of the principle type 1 interferon-producing cells in human blood. Science 1999;284:1835–1837.PubMedCrossRefGoogle Scholar
  18. 18.
    Cella M, Jarrossay D, Facchetti F et al.: Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type-1 interferon. Nat Med 1999; 5:919–923.PubMedCrossRefGoogle Scholar
  19. 19.
    Maraskovsky E, Brasel K, Teepe M et al.: Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. J Exp Med 1996;184: 1953–1962.PubMedCrossRefGoogle Scholar
  20. 20.
    Pulendran B, Lingappa J, Kennedy MK et al.: Developmental pathways of dendritic cells in vivo: distinct function, phenotype, and localization of dendritic cell subsets in FLT3 ligand- treated mice. J Immunol 1997;159: 2222–2231.PubMedGoogle Scholar
  21. 21.
    Shurin MR, Pandharipande PP, Zorina TD et al.: FLT3 ligand induces the generation of functionally active dendritic cells in mice. Cell Immunol 1997;179:174–184.PubMedCrossRefGoogle Scholar
  22. 22.
    Pulendran B, Smith J, Jenkins M et al.: Prevention of peripheral tolerance by a dendritic cell growth factor: flt3 ligand as an adjuvant. J Exp Med 1998;188:2075–2082.PubMedCrossRefGoogle Scholar
  23. 23.
    Maraskovsky E, Daro E, Roux E et al.: In vivo generation of human dendritic cell subsets by Flt3-Ligand. Blood 2000;96:878–884.PubMedGoogle Scholar
  24. 24.
    Pulendran, B, Banchereau J, Burkeholder S et al.: Flt3-Ligand and G-CSF mobilize distinct human DC subsets in vivo. J Immunol 2000;165:566–572.PubMedGoogle Scholar
  25. 25.
    Iwasaki A. and Kelsall, B.L.: Freshly isolated Peyer's patch, but not spleen, dendritic cells produce interleukin 10 and induce the differentiation of T helper type 2 cells. J Exp Med 1999;190:229–239.PubMedCrossRefGoogle Scholar
  26. 26.
    Sousa CR, Hieny S, Scharton-Kersten T et al.: In vivo microbial stimulation induces rapid CD40 ligand-independent production of interleukin 12 by dendritic cells and their redistribution to T cell areas. J Exp Med 1997;186:1819–1829.CrossRefGoogle Scholar
  27. 27.
    Ohteki T, Fukao T, Suzue K et al.: Interleukin 12-dependent interferon gamma production by CD8alpha+ lymphoid dendritic cells. J Exp Med 1999;189:1981–1986.PubMedCrossRefGoogle Scholar
  28. 28.
    Maldanado-Lopez R., Maliszewski C, Urbain J et al.: Cytokines regulate the capacity of CD8alpha(+) and CD8alpha(−) dendritic cells to prime Th1/Th2 cells in vitro. J Immunol 2001;167:4345–4350.Google Scholar
  29. 29.
    Tanaka H, Demeure CE, Rubio M et al.: Human monocyte-derived dendritic cells induce naive T cell differentiation into T helper cell type 2 (Th2) or Th1/Th2 effectors. Role of stimulator/responder ratio. J Exp Med 2000;192:405–412.PubMedCrossRefGoogle Scholar
  30. 30.
    Kadowaki N, Antonenko S, Lau JY et al.: Natural interferon-alpha/beta producing cells link innate and adaptive immunity. J Exp Med 2000;192:219–226.PubMedCrossRefGoogle Scholar
  31. 31.
    d'Ostiani CF, Del Sero G, Bacci A et al.: Dendritic cells discriminate between yeasts and hyphae of the fungus Candida albicans. Implications for initiation of T helper immunity in vitro and in vivo. J Exp Med 2000;191:1661–1674.PubMedCrossRefGoogle Scholar
  32. 32.
    Pulendran B, Kumar P, Cutler CW et al.: Lipopolysaccharides from distinct pathogens induce different classes of immune responses in vivo. J Immunol 2001;167: 5067–5076.PubMedGoogle Scholar
  33. 33.
    MacDonald, A.S., Straw, A.D., Bauman, B., Pearce, E.J.: CD8-dendritic cell activation status plays an integral role in influencing Th2 response development. J Immunol 2001;167:1982–1988.PubMedGoogle Scholar
  34. 34.
    Whelan M, Harrett MM, Houston KM et al.: A filarial nematode-secreted product signals dendritic cells to acquire a phenotype that drives development of Th2 cells. J Immunol 2000;15:6453–6460.Google Scholar
  35. 35.
    Braun MC, He J, Wu CJ et al.: Cholera toxin suppresses interleukin (IL)-12 production and IL-12 receptor betal and beta2 chain expression. J Exp Med 1999;189:541–552.PubMedCrossRefGoogle Scholar
  36. 36.
    Tzou P De Gregorio E, Lemaitre B: How Drosophila combals microbial infection: a model to study innate immunity and host-pathogen interactions. Curr Opin Microbiol 2002;5:102–110.PubMedCrossRefGoogle Scholar
  37. 37.
    Janeway CA Jr, Mezhitov R: Innate Immune Recognition. Annu Rev Immunol 2002;20:197–216.PubMedCrossRefGoogle Scholar
  38. 38.
    Hoffman JA, Mafatos FC, Janeway CA et al.: Phylogenetic perspectives in immunity. Science 1999;284:1313–1318.CrossRefGoogle Scholar
  39. 39.
    Hirschfeld M, Weis JJ, Toshchakov V et al.: Signaling by toll-like receptor 2 and 4 agonists results in differential gene expression in murine macrophages. Infect & Immunity 2001;69:1477–1482.CrossRefGoogle Scholar
  40. 40.
    Re F, Strominger JL: Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells. J Biol Chem 2001;276:37692–37699.PubMedCrossRefGoogle Scholar
  41. 41.
    Ogawa T, AsaiY, Hashimoto M et al.: Cell activation by Porphyromonas gingivalis lipid A molecule through Toll-like receptor 4- and myeloid differentiation factor 88-dependent signaling pathway. Int Immunol 2002;14: 1325–1332.PubMedCrossRefGoogle Scholar
  42. 42.
    Agrawal S, Agrawal A, Doughty B et al.: Cutting edge: different Toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos. J Immunol 2003 171(10):4984–4989.PubMedGoogle Scholar
  43. 43.
    Dillon S, Agrawal A, Van Dyke T et al.: A Toll-Like Receptor 2 Ligand Stimulates Th2 Responses In Vivo, Via Induction of Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and c-Fos in Dendritic Cells. J Immunol 2004: (April 15-in press).Google Scholar
  44. 44.
    Van Die I, Van Vliet SJ, Nyame AK et al.: The dendritic cell-specific C-type lectin DC-SIGN is a receptor for Schistosoma mansoni egg antigens and recognizes the glycan antigen Lewis x. Glycobiology 13(6):471–478.Google Scholar
  45. 45.
    Stumbles PA, Thomas JA, Pimm CL et al.: Resting respiratory tract dendritic cells preferentially stimulate T helper cell type 2 (Th2) responses and require obligatory cytokine signals for induction of Th1 immunity. J Exp Med 1998;188:2019–2031.PubMedCrossRefGoogle Scholar
  46. 46.
    Soumelis V, Reche PA, Kanzler H et al.: 2002. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 3(7): 673–680.PubMedGoogle Scholar
  47. 47.
    Kadowaki B, 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 Med 2001;194:863–869.PubMedCrossRefGoogle Scholar
  48. 48.
    Jarrossay D, Napolitani G, Colonna M. et al.: Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. Eur J Immunol 2001;31:3388–3393.PubMedCrossRefGoogle Scholar
  49. 49.
    Barchet W, Cella M, Odermatt, B et al.: Virus-induced Interferon α Production by a Dendritic Cell Subset in the Absence of Feedback Signaling In Vivo. J Exp Med 2002;195:507–516.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2004

Authors and Affiliations

  • Bali Pulendran
    • 1
    • 2
  1. 1.Department of PathologyAtlanta
  2. 2.Emory Maccine CenterAtlanta

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