Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria

Abstract

Penetration of the gut mucosa by pathogens expressing invasion genes is believed to occur mainly through specialized epithelial cells, called M cells, that are located in Peyer's patches. However, Salmonella typhimurium that are deficient in invasion genes encoded by Salmonella pathogenicity island 1 (SPI1) are still able to reach the spleen after oral administration. This suggests the existence of an alternative route for bacterial invasion, one that is independent of M cells. We report here a new mechanism for bacterial uptake in the mucosa tissues that is mediated by dendritic cells (DCs). DCs open the tight junctions between epithelial cells, send dendrites outside the epithelium and directly sample bacteria. In addition, because DCs express tight-junction proteins such as occludin, claudin 1 and zonula occludens 1, the integrity of the epithelial barrier is preserved.

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Figure 1: DCs induce transcytosis of fluorescent bacteria across a monolayer of differentiated human Caco-2 cells.
Figure 2: DCs cross the filter and infiltrate the epithelial monolayer.
Figure 3: DCs can uptake bacteria directly through a monolayer of epithelial cells.
Figure 4: DCs express proteins involved in the formation of TJs.
Figure 5: DCs are recruited at the site of infection in vivo.
Figure 6: In the presence of bacteria, DCs creep between epithelial cells and send dendrites out to the intestinal lumen in vivo.
Figure 7: DCs are recruited in the intestine and can also uptake nonpathogenic E. coli.
Figure 8: Scheme of the events occurring during a bacterial infection.

References

  1. 1

    Farquhar, M. G. & Palade, G. E. Junctional complexes in various epithelia. J. Cell Biol. 17, 375–412 (1963).

    CAS  Article  Google Scholar 

  2. 2

    Madara, J. L., Nash, S., Moore, R. & Atisook, K. Structure and function of the intestinal epithelial barrier in health and disease. Monogr. Pathol. 306–324 (1990).

  3. 3

    Inman, L. R. & Cantey, J. R. Specific adherence of Escherichia coli (strain RDEC-1) to membranous (M) cells of the Peyer's patch in Escherichia coli diarrhea in the rabbit. J. Clin. Invest. 71, 1–8 (1983).

    CAS  Article  Google Scholar 

  4. 4

    Wassef, J. S., Keren, D. F. & Mailloux, J. L. Role of M cells in initial antigen uptake and in ulcer formation in the rabbit intestinal loop model of shigellosis. Infect. Immun. 57, 858–863 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Kohbata, S., Yokoyama, H. & Yabuuchi, E. Cytopathogenic effect of Salmonella typhi GIFU 10007 on M cells of murine ileal Peyer's patches in ligated ileal loops: an ultrastructural study. Microbiol. Immunol. 30, 1225–1237 (1986).

    CAS  Article  Google Scholar 

  6. 6

    Neutra, M. R., Pringault, E. & Kraehenbuhl, J. P. Antigen sampling across epithelial barriers and induction of mucosal immune responses. Ann. Rev. Immunol. 14, 275–300 (1996).

    CAS  Article  Google Scholar 

  7. 7

    Galan, J. E. & Curtiss, R. D. Cloning and molecular characterization of genes whose products allow Salmonella typhimurium to penetrate tissue culture cells. Proc. Natl Acad. Sci. USA 86, 6383–6387 (1989).

    CAS  Article  Google Scholar 

  8. 8

    Vazquez-Torres, A. et al. Extraintestinal dissemination of Salmonella by CD18-expressing phagocytes. Nature 401, 804–808 (1999).

    CAS  Article  Google Scholar 

  9. 9

    Banchereau, J. & Steinman, R. M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).

    CAS  Article  Google Scholar 

  10. 10

    Rescigno, M., Granucci, F., Citterio, S., Foti, M. & Ricciardi-Castagnoli, P. Coordinated events during bacteria-induced DCS maturation. Immunol. Today 20, 200–203 (1999).

    CAS  Article  Google Scholar 

  11. 11

    Huang, F. P. et al. A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes. J. Exp. Med. 191, 435–444 (2000).

    CAS  Article  Google Scholar 

  12. 12

    Ruedl, C. & Hubele, S. Maturation of Peyer's patch dendritic cells in vitro upon stimulation via cytokines or CD40 triggering. Eur. J. Immunol. 27, 1325–1330 (1997).

    CAS  Article  Google Scholar 

  13. 13

    Kelsall, B. L. & Strober, W. Distinct populations of dendritic cells are present in the subepithelial dome and T cell regions of the murine Peyer's patch. J. Exp. Med. 183, 237–247 (1996).

    CAS  Article  Google Scholar 

  14. 14

    Iwasaki, A. & Kelsall, B. L. Localization of distinct Peyer's patch dendritic cell subsets and their recruitment by chemokines macrophage inflammatory protein (MIP)-3α, MIP-3β, and secondary lymphoid organ chemokine. J. Exp. Med. 191, 1381–1394 (2000).

    CAS  Article  Google Scholar 

  15. 15

    Maric, I., Holt, P. G., Perdue, M. H. & Bienstock, J. Class II MHC antigen (Ia)-bearing dendritic cells in the epithelium of the rat intestine J. Immunol. 156, 1408–1414 (1996)

    CAS  PubMed  Google Scholar 

  16. 16

    Hopkins, S., Niedergang, F., Corthésy-Theulaz, I. E. & Kraehenbuhl, J. P. A recombinant Salmonella typhimurium vaccine strain is taken up and survives within murine Peyer's patch dendritic cells. Cell. Microbiol. 2, 56–68 (2000).

    Article  Google Scholar 

  17. 17

    Winzler, C. et al. Maturation stages of mouse dendritic cells in growth factor-dependent long-term cultures. J. Exp. Med. 185, 317–328 (1997).

    CAS  Article  Google Scholar 

  18. 18

    Rescigno, M. et al. Bacteria-induced neo-biosynthesis, stabilization, and surface expression of functional class I molecules in mouse dendritic cells. Proc. Natl Acad. Sci. USA 95, 5229–5234 (1998).

    CAS  Article  Google Scholar 

  19. 19

    Brown, A. et al. An attenuated aroA Salmonella typhimurium vaccine elicits humoral and cellular immunity to cloned β-galactosidase in mice. J. Infect. Dis. 155, 86–92 (1987).

    CAS  Article  Google Scholar 

  20. 20

    Pozzi, G. et al. Methods and parameters for genetic transformation of S. gordonii. Res. Microbiol. 141, 659–670 (1990).

    CAS  Article  Google Scholar 

  21. 21

    Kerneis, S., Bogdanova, A., Kraehenbuhl, J. P. & Pringault, E. Conversion by Peyer's patch lymphocytes of human enterocytes into M cells that transport bacteria. Science 277, 949–952 (1997).

    CAS  Article  Google Scholar 

  22. 22

    Rescigno, M. et al. in Dendritic Cell: Biology and clinical applications (ed. Thomson, M. L. a. A.) 403–419 (Academic Press, San Diego, CA, 1999).

    Google Scholar 

  23. 23

    Austyn, J. M. New insights into the mobilization and phagocytic activity of dendritic cells. J. Exp. Med. 183, 1287–1292 (1996).

    CAS  Article  Google Scholar 

  24. 24

    Tsukita, S., Furuse, M. & Itoh, M. Structural and signalling molecules come together at tight junctions. Curr. Opin. Cell Biol. 11, 628–633 (1999).

    CAS  Article  Google Scholar 

  25. 25

    Rajasekaran, A. K., Hojo, M., Huima, T. & Rodriguez-Boulan, E. Catenins and zonula occludens-1 form a complex during early stages in the assembly of tight junctions. J. Cell Biol. 132, 451–463 (1996).

    CAS  Article  Google Scholar 

  26. 26

    Wong, V. & Gumbiner, B. M. A synthetic peptide corresponding to the extracellular domain of occludin perturbs the tight junction permeability barrier. J. Cell Biol. 136, 399–409 (1997).

    CAS  Article  Google Scholar 

  27. 27

    Mowat, A. M. & Viney, J. L. The anatomical basis of intestinal immunity. Immunol Rev 156, 145–166 (1997).

    CAS  Article  Google Scholar 

  28. 28

    Dieu-Nosjean, M. C. et al. Macrophage inflammatory protein 3α is expressed at inflamed epithelial surfaces and is the most potent chemokine known in attracting Langerhans cell precursors. J. Exp. Med. 192, 705–718 (2000).

    CAS  Article  Google Scholar 

  29. 29

    Forster, R. et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99, 23–33 (1999).

    CAS  Article  Google Scholar 

  30. 30

    Huber, D., Balda, M. S. & Matter, K. Occludin modulates transepithelial migration of neutrophils. J. Biol. Chem. 275, 5773–5778 (2000).

    CAS  Article  Google Scholar 

  31. 31

    Del Maschio, A. et al. Leukocyte recruitment in the cerebrospinal fluid of mice with experimental meningitis is inhibited by an antibody to junctional adhesion molecule (JAM). J. Exp. Med. 190, 1351–1356 (1999).

    CAS  Article  Google Scholar 

  32. 32

    Monack, D. M. et al. Salmonella exploits caspase-1 to colonize Peyer's patches in a murine typhoid model. J. Exp. Med. 192, 249–258 (2000).

    CAS  Article  Google Scholar 

  33. 33

    Macpherson, A. J. et al. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 288, 2222–2226 (2000).

    CAS  Article  Google Scholar 

  34. 34

    Gasperi, C. et al. Retroviral gene transfer, rapid selection, and maintenance of the immature phenotype in mouse dendritic cells. J. Leuko. Biol. 66, 263–267 (1999).

    CAS  Article  Google Scholar 

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Acknowledgements

We thank K. Giese (Atugen, Berlin) for the TaqMan analysis on occludin mRNA and R. Steinman and D. Grdic for helpful discussions. Supported by grants from the Italian Association against Cancer (AIRC); the National Research Council (CNR Project in Biotechnology); the EC contract MUCIMM; and the Swiss National Science Foundation.

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Correspondence to Paola Ricciardi-Castagnoli.

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Rescigno, M., Urbano, M., Valzasina, B. et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol 2, 361–367 (2001). https://doi.org/10.1038/86373

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