Skip to main content Accessibility help
  • Print publication year: 2007
  • Online publication date: August 2009

4 - Dendritic cell activation and uptake of bacteria in vivo

from II - Dendritic cells and innate immune responses to bacteria



Pathogenic bacteria have evolved several strategies to gain access across epithelial surfaces particularly those lining the mucosae. After their epithelial transcytosis bacteria find a first line of immune defense represented by professional phagocytes, including macrophages and dendritic cells. These cells are particularly apt at bacterial uptake, killing and processing for the initiation/maintenance of adaptive immune responses. Furthermore, intracellular bacteria can induce by epithelial cells the release of inflammatory mediators and cytokines that will recruit other immune cells, particularly neutrophils. Dendritic cells are not simply passive players waiting for possible invaders, they can actively participate to bacterial sampling by intercalating between epithelial cells. This mechanism is not restricted to pathogenic bacteria. Since gut dendritic cells have been thoroughly studied, in this chapter we will focus on dendritic cells located in the intestinal mucosa and on their role in the uptake and handling of luminal bacteria.


The intestinal epithelium is the first line of defense toward dangerous microorganisms. It opposes a physical, electric and chemical barrier against luminal bacteria. The permeability of the barrier is regulated by the presence of both tight junctions (TJ) between epithelial cells (ECs) and a negatively charged mucous glycocalix. TJ seal adjacent ECs to one another and regulate solute and ion flux between cells. The glycocalix sets the size of macromolecules that can reach the apical membrane of ECs and opposes an electric barrier to bacteria.

Sansonetti, P. J. (2004). War and peace at mucosal surfaces. Nat. Rev. Immunol. 4, 953–64.
Mowat, A. M. (2003). Anatomical basis of tolerance and immunity to intestinal antigens. Nat. Rev. Immunol. 3, 331–41.
Schneeberger, E. E. and Lynch, R. D. (2004). The tight junction: a multifunctional complex. Am. J. Physiol. Cell Physiol. 286, C1213–28.
Frey, A., Giannasca, K. T., Weltzin, R., Giannasca, P. J., Reggio, H., Lencer, W. I. and Neutra, M. R. (1996). Role of the glycocalyx in regulating access of microparticles to apical plasma membranes of intestinal epithelial cells: implications for microbial attachment and oral vaccine targeting. J. Exp. Med. 184, 1045–59.
Ganz, T. (2003). Defensins: antimicrobial peptides of innate immunity. Nat. Rev. Immunol. 3, 710–20.
Kraehenbuhl, J. P. and Neutra, M. R. (2000). Epithelial M cells: differentiation and function. Annu. Rev. Cell Dev. Biol. 16, 301–32.
Banchereau, J., Briere, F., Caux, C., Davoust, J., Lebecque, S., Liu, Y. J., Pulendran, B. and Palucka, K. (2000). Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811.
Bilsborough, J. and Viney, J. L. (2004). Gastrointestinal dendritic cells play a role in immunity, tolerance, and disease. Gastroenterology 127, 300–9.
Kelsall, B. L. and Rescigno, M. (2004). Mucosal dendritic cells in immunity and inflammation. Nat. Immunol. 5, 1091–5.
Jang, M. H., Kweon, M. N., Iwatani, K., Yamamoto, M., Terahara, K., Sasakawa, C., Suzuki, T., Nochi, T., Yokota, Y., Rennert, P. al. (2004). Intestinal villous M cells: an antigen entry site in the mucosal epithelium. Proc. Natl Acad. Sci. U S A 101, 6110–15.
Maric, I., Holt, P. G., Perdue, M. H. and Bienenstock, J. (1996). Class II major histocompatibility complex antigen (Ia)-bearing dendritic cells in the epithelium of the rat intestine. J. Immunol. 156, 1408–14.
Rescigno, M., Urbano, M., Valzasina, B., Francolini, M., Rotta, G., Bonasio, R., Granucci, F., Kraehenbuhl, J. P. and Ricciardi-Castagnoli, P. (2001). Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat. Immunol. 2, 361–7.
Rescigno, M., Rotta, G., Valzasina, B. and Ricciardi-Castagnoli, P. (2001). Dendritic cells shuttle microbes across gut epithelial monolayers. Immunobiology 204, 572–81.
Niess, J. H., Brand, S., Gu, X., Landsman, L., Jung, S., McCormick, B. A., Vyas, J. M., Boes, M., Ploegh, H. L., Fox, J. al. (2005). CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307, 254–8.
Rimoldi, M., Chieppa, M., Vulcano, M., Allavena, P. and Rescigno, M. (2004). Intestinal epithelial cells control dendritic cell function. Ann. N Y Acad. Sci. 1029, 1–9.
Nagler-Anderson, C. (2001). Man the barrier! Strategic defences in the intestinal mucosa. Nat. Rev. Immunol. 1, 59–67.
Viney, J. L., Mowat, A. M., O'Malley, J. M., Williamson, E. and Fanger, N. A. (1998). Expanding dendritic cells in vivo enhances the induction of oral tolerance. J. Immunol. 160, 5815–25.
Kunkel, D., Kirchhoff, D., Nishikawa, S., Radbruch, A. and Scheffold, A. (2003). Visualization of peptide presentation following oral application of antigen in normal and Peyer's patches-deficient mice. Eur. J. Immunol. 33, 1292–301.
Kunisawa, J., Takahashi, I., Okudaira, A., Hiroi, T., Katayama, K., Ariyama, T., Tsutsumi, Y., Nakagawa, S., Kiyono, H. and Mayumi, T. (2002). Lack of antigen-specific immune responses in anti-interleukin-7 receptor alpha chain antibody-treated Peyer's patch-null mice following intestinal immunization with microencapsulated antigen. Eur. J. Immunol. 32, 2347–55.
Macpherson, A. J. and Uhr, T. (2004). Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 303, 1662–5.
Yoshida, M., Claypool, S. M., Wagner, J. S., Mizoguchi, E., Mizoguchi, A., Roopenian, D. C., Lencer, W. I. and Blumberg, R. S. (2004). Human neonatal Fc receptor mediates transport of IgG into luminal secretions for delivery of antigens to mucosal dendritic cells. Immunity 20, 769–83.
Weltzin, R., Lucia-Jandris, P., Michetti, P., Fields, B. N., Kraehenbuhl, J. P., and Neutra, M. R. (1989). Binding and transepithelial transport of immunoglobulins by intestinal M cells: demonstration using monoclonal IgA antibodies against enteric viral proteins. J. Cell Biol. 108, 1673–85.
Rey, J., Garin, N., Spertini, F. and Corthesy, B. (2004). Targeting of secretory IgA to Peyer's patch dendritic and T cells after transport by intestinal M cells. J. Immunol. 172, 3026–33.
Huang, F. P., Platt, N., Wykes, M., Major, J. R., Powell, T. J., Jenkins, C. D. and MacPherson, G. G. (2000). A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes, see comments. J. Exp. Med. 191, 435–44.
Fleeton, M. N., Contractor, N., Leon, F., Wetzel, J. D., Dermody, T. S. and Kelsall, B. L. (2004). Peyer's patch dendritic cells process viral antigen from apoptotic epithelial cells in the intestine of reovirus-infected mice. J. Exp. Med. 200, 235–45.
Shortman, K. and Liu, Y. J. (2002). Mouse and human dendritic cell subtypes. Nat. Rev. Immunol. 2, 151–61.
Iwasaki, A. and Kelsall, B. L. (2000). Localization of distinct Peyer's patch dendritic cell subsets and their recruitment by chemokines macrophage inflammatory protein (MIP)-3alpha, MIP-3beta, and secondary lymphoid organ chemokine. J. Exp. Med. 191, 1381–94.
Niedergang, F., Didierlaurent, A., Kraehenbuhl, J. P. and Sirard, J. C. (2004). Dendritic cells: the host Achille's heel for mucosal pathogens?Trends Microbiol. 12, 79–88.
Bell, S. J., Rigby, R., English, N., Mann, S. D., Knight, S. C., Kamm, M. A. and Stagg, A. J. (2001). Migration and maturation of human colonic dendritic cells. J. Immunol. 166, 4958–67.
Viala, J., Chaput, C., Boneca, I. G., Cardona, A., Girardin, S. E., Moran, A. P., Athman, R., Memet, S., Huerre, M. R., Coyle, A. al. (2004). Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat. Immunol. 5, 1166–74.
Lala, S., Ogura, Y., Osborne, C., Hor, S. Y., Bromfield, A., Davies, S., Ogunbiyi, O., Nunez, G. and Keshav, S. (2003). Crohn's disease and the nucleotide-binding oligomerization domain2 gene: a role for paneth cells. Gastroenterology 125, 47–57.
Rosenstiel, P., Fantini, M., Brautigam, K., Kuhbacher, T., Waetzig, G. H., Seegert, D. and Schreiber, S. (2003). Tnuclear factor-alpha and interferon-gamma regulate the expression of the nucleotide-binding oligomerization domain2 (CARD15) gene in human intestinal epithelial cells. Gastroenterology 124, 1001–9.
Gutierrez, O., Pipaon, C., Inohara, N., Fontalba, A., Ogura, Y., Prosper, F., Nunez, G. and Fernandez-Luna, J. L. (2002). Induction of Nod2 in myelomonocytic and intestinal epithelial cells via nuclear factor-kappa B activation. J. Biol. Chem. 277, 41701–5.
Eckmann, L., Kagnoff, M. F. and Fierer, J. (1993). Epithelial cells secrete the chemokine interleukin-8 in response to bacterial entry. Infect. Immun. 61, 4569–74.
Jung, H. C., Eckmann, L., Yang, S. K., Panja, A., Fierer, J., Morzycka-Wroblewska, E. and Kagnoff, M. F. (1995). A distinct array of proinflammatory cytokines is expressed in human colon epithelial cells in response to bacterial invasion. J. Clin. Invest. 95, 55–65.
McCormick, B. A., Colgan, S. P., Delp-Archer, C., Miller, S. I. and Madara, J. L. (1993). Salmonella typhimuriumattachment to human intestinal epithelial monolayers: transcellular signalling to subepithelial neutrophils. J. Cell Biol. 123, 895–907.
McCormick, B. A., Hofman, P. M., Kim, J., Carnes, D. K., Miller, S. I. and Madara, J. L. (1995). Surface attachment ofSalmonella typhimurium to intestinal epithelia imprints the subepithelial matrix with gradients chemotactic for neutrophils. J. Cell Biol. 131, 1599–608.
Hayashi, F., Smith, K. D., Ozinsky, A., Hawn, T. R., Yi, E. C., Goodlett, D. R., Eng, J. K., Akira, S., Underhill, D. M. and Aderem, A. (2001). The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410, 1099–103.
Sierro, F., Dubois, B., Coste, A., Kaiserlian, D., Kraehenbuhl, J. P. and Sirard, J. C. (2001). Flagellin stimulation of intestinal epithelial cells triggers CCL20-mediated migration of dendritic cells. Proc. Natl. Acad. Sci. U S A 98, 13722–7.
Sozzani, S., Allavena, P., D'Amico, G., Luini, W., Bianchi, G., Kataura, M., Imai, T., Yoshie, O., Bonecchi, R. and Mantovani, A. (1998). Differential regulation of chemokine receptors during dendritic cell maturation: a model for their trafficking properties. J. Immunol. 161, 1083–6.
Gewirtz, A. T., Simon, P. O. Jr., Schmitt, C. K., Taylor, L. J., Hagedorn, C. H., O'Brien, A. D., Neish, A. S. and Madara, J. L. (2001). Salmonella typhimuriumtranslocates flagellin across intestinal epithelia, inducing a proinflammatory response. J. Clin. Invest. 107, 99–109.
Lyons, S., Wang, L., Casanova, J. E., Sitaraman, S. V., Merlin, D. and Gewirtz, A. T. (2004). Salmonella typhimuriumtranscytoses flagellin via an SPI2-mediated vesicular transport pathway. J. Cell Sci. 117, 5771–80.
Ramos, H. C., Rumbo, M. and Sirard, J. C. (2004). Bacterial flagellins: mediators of pathogenicity and host immune responses in mucosa. Trends Microbiol. 12, 509–17.
Rimoldi, M., Chieppa, M., Larghi, P., Vulcano, M., Allavena, P. and Rescigno, M. (2005). Monocyte-derived dendritic cells activated by bacteria or by bacteria-stimulated epithelial cells are functionally different. Blood 106, 2818–26.
Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. and Medzhitov, R. (2004). Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 118, 229–41.
Kobayashi, K., Hernandez, L. D., Galan, J. E., Janeway, C. A. Jr., Medzhitov, R. and Flavell, R. A. (2002). interleukin-1R-associated kinase-M is a negative regulator of Toll-like receptor signaling. Cell 110, 191–202.
Janssens, S., Burns, K., Tschopp, J. and Beyaert, R. (2002). Regulation of interleukin-1- and lipopolysaccharide-induced nuclear factor-kappaB activation by alternative splicing of MyD88. Curr. Biol. 12, 467–71.
Kelly, D., Campbell, J. I., King, T. P., Grant, G., Jansson, E. A., Coutts, A. G., Pettersson, S. and Conway, S. (2004). Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of peroxisome-proliferator-activated receptor-gamma and RelA. Nat. Immunol. 5, 104–12.
Neish, A. S., Gewirtz, A. T., Zeng, H., Young, A. N., Hobert, M. E., Karmali, V., Rao, A. S. and Madara, J. L. (2000). Prokaryotic regulation of epithelial responses by inhibition of IkappaB-alpha ubiquitination. Science 289, 1560–3.
Akbari, O., DeKruyff, R. H. and Umetsu, D. T. (2001). Pulmonary dendritic cells producing interleukin-10 mediate tolerance induced by respiratory exposure to antigen. Nat. Immunol. 2, 725–31.
Alpan, O., Rudomen, G. and Matzinger, P. (2001). The role of dendritic cells, B cells, and M cells in gut-oriented immune responses. J. Immunol. 166, 4843–52.
Iwasaki, A. and Kelsall, B. L. (1999). 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. 190, 229–39.
Williamson, E., Bilsborough, J. M. and Viney, J. L. (2002). Regulation of mucosal dendritic cell function by receptor activator of nuclear factor-kappa B (RAnatural killer)/RAnatural killer ligand interactions: impact on tolerance induction. J. Immunol. 169, 3606–12.
Iwasaki, A. and Kelsall, B. L. (2001). Unique functions of cd11b(+), cd8alpha(+), and double-negative Peyer's patch dendritic cells. J. Immunol. 166, 4884–90.
Sato, A., Hashiguchi, M., Toda, E., Iwasaki, A., Hachimura, S. and Kaminogawa, S. (2003). CD11b+ Peyer's patch dendritic cells secrete interleukin-6 and induce IgA secretion from naive B cells. J. Immunol. 171, 3684–90.
Stagg, A. J., Kamm, M. A. and Knight, S. C. (2002). Intestinal dendritic cells increase T cell expression of alpha4beta7 integrin. Eur. J. Immunol. 32, 1445–54.
Mora, J. R., Bono, M. R., Manjunath, N., Weninger, W., Cavanagh, L. L., Rosemblatt, M. and Andrian, U. H. (2003). Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature 424, 88–93.
Johansson-Lindbom, B., Svensson, M., Wurbel, M. A., Malissen, B., Marquez, G. and Agace, W. (2003). Selective generation of gut tropic T cells in gut-associated lymphoid tissue (gut associated lymphoid tissue): requirement for gut associated lymphoid tissue dendritic cells and adjuvant. J. Exp. Med. 198, 963–9.
Mora, J. R., Cheng, G., Picarella, D., Briskin, M., Buchanan, N. and Andrian, U. H. (2005). Reciprocal and dynamic control of CD8 T cell homing by dendritic cells from skin- and gut-associated lymphoid tissues. J. Exp. Med. 201, 303–16.
Yrlid, U. and Macpherson, G. (2003). Phenotype and function of rat dendritic cell subsets. Apmis 111, 756–65.
Turnbull, E. L., Yrlid, U., Jenkins, C. D. and Macpherson, G. G. (2005). Intestinal dendritic cell subsets: differential effects of systemic Toll-like receptor4 stimulation on migratory fate and activation in vivo. J. Immunol. 174, 1374–84.
Smits, H. H., Beelen, A. J., Hessle, C., Westland, R., Jong, E., Soeteman, E., Wold, A., Wierenga, E. A. and Kapsenberg, M. L. (2004). Commensal Gram-negative bacteria prime human dendritic cells for enhanced interleukin-23 and interleukin-27 expression and enhanced Th1 development. Eur. J. Immunol. 34, 1371–80.
Smits, H. H., Engering, A., Kleij, D., Jong, E. C., Schipper, K., Capel, T. M., Zaat, B. A., Yazdanbakhsh, M., Wierenga, E. A., Kooyk, Y. and Kapsenberg, M. L. (2005). Selective probiotic bacteria induce interleukin-10-producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin. J. Allergy Clin. Immunol. 115, 1260–7.
Svensson, M., Maroof, A., Ato, M. and Kaye, P. M. (2004). Stromal cells direct local differentiation of regulatory dendritic cells. Immunity 21, 805–16.
Zhang, M., Tang, H., Guo, Z., An, H., Zhu, X., Song, W., Guo, J., Huang, X., Chen, T., Wang, J. and Cao, X. (2004). Splenic stroma drives mature dendritic cells to differentiate into regulatory dendritic cells. Nat. Immunol. 5, 1124–33.
Soumelis, V. and Liu, Y. J. (2004). Human thymic stromal lymphopoietin: a novel epithelial cell-derived cytokine and a potential key player in the induction of allergic inflammation. Springer Semin. Immunopathol. 25, 325–33.
Soumelis, V., Reche, P. A., Kanzler, H., Yuan, W., Edward, G., Homey, B., Gilliet, M., Ho, S., Antonenko, S., Lauerma, al. (2002). Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing thymic stromal lymphopoietin. Nat. Immunol. 3, 673–80.
Rimoldi, M., Chieppa, M., Salucci, V., Avogadri, F., Sonzogni, A., Sampietro, G. M., Nespoli, A., Viale, G., Allavena, P. and Rescigno, M. (2005). Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nat. Immunol. 6, 507–14.
Kosiewicz, M. M., Nast, C. C., Krishnan, A., Rivera-Nieves, J., Moskaluk, C. A., Matsumoto, S., Kozaiwa, K. and Cominelli, F. (2001). Th1-type responses mediate spontaneous ileitis in a novel murine model of Crohn's disease. J. Clin. Invest. 107, 695–702.
Mastroeni, P. and Menager, N. (2003). Development of acquired immunity toSalmonella. J. Med. Microbiol. 52, 453–9.
Hess, J., Ladel, C., Miko, D. and Kaufmann, S. H. (1996). Salmonella typhimuriumaroA– infection in gene-targeted immunodeficient mice: major role of CD4+ TCR-alpha beta cells and interferon-gamma in bacterial clearance independent of intracellular location. J. Immunol. 156, 3321–6.
George, A. (1996). Generation of gamma interferon responses in murine Peyer's patches following oral immunization. Infect. Immun. 64, 4606–11.
Liesenfeld, O., Kosek, J. C. and Suzuki, Y. (1997). Gamma interferon induces Fas-dependent apoptosis of Peyer's patch T cells in mice following peroral infection withToxoplasma gondii. Infect. Immun. 65, 4682–9.
Vossenkamper, A., Struck, D., Alvarado-Esquivel, C., Went, T., Takeda, K., Akira, S., Pfeffer, K., Alber, G., Lochner, M., Forster, I. and Liesenfeld, O. (2004). Both interleukin-12 and interleukin-18 contribute to small intestinal Th1-type immunopathology following oral infection withToxoplasma gondii, but interleukin-12 is dominant over interleukin-18 in parasite control. Eur. J. Immunol. 34, 3197–207.