Collaboration of epithelial cells with organized mucosal lymphoid tissues


Immune surveillance of mucosal surfaces requires the delivery of intact macromolecules and microorganisms across epithelial barriers to organized mucosal lymphoid tissues. Transport, processing and presentation of foreign antigens, as well as local induction and clonal expansion of antigen-specific effector lymphocytes, involves a close collaboration between organized lymphoid tissues and the specialized follicle-associated epithelium. M cells in the follicle-associated epithelium transport foreign macromolecules and microorganisms to antigen-presenting cells within and under the epithelial barrier. Determination of the earliest cellular interactions that occur in and under the follicle-associated epithelium could greatly facilitate the design of effective mucosal vaccines in the future.

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Figure 1: Association of FAE with cells of the mucosal immune system in rabbit Peyer's patches.
Figure 2: Secretory IgA: possible role in sampling of antigens by M cells.
Figure 3: Fates of antigens and pathogens after M cell transport.


  1. 1

    Forstner, J. F., Oliver, M. G. & Sylvester, F. A. in Infections of the Gastrointestinal Tract (eds Blaser, M., Smith, P. D., Ravdin, J. I., Greenberg, H. B. & Guerrant, R. L.) 71–88 (Raven Press, New York, 1995).

  2. 2

    Ouellette, A. & Selsted, M. E. Paneth cell defensins: endogenous components of intestinal host defense. FASEB J. 10, 1280–1289 (1996).

  3. 3

    Lamm, M. E. Interactions of antigens and antibodies at mucosal surfaces. Annu. Rev. Microbiol. 51, 311–340 (1997).

  4. 4

    Madara, J. L., Nash, S., Moore, R. & Atisook, K. Structure and function of the intestinal epithelial barrier in health and disease. Monogr. Pathol. 31, 306–324 (1990).

  5. 5

    Frey, A. et al. Role of the glycocalyx in regulating access of microparticles to apical plasma membranes of intestinal epithelial cells: Implications for microbial attachment and vaccine targeting. J. Exp. Med. 184, 1045–1059 (1996).

  6. 6

    Brandtzaeg, P. et al. Regional specialization in the mucosal immune system: what happens in the microcompartments? Immunol. Today 20, 141–151 (1999).

  7. 7

    Kraehenbuhl, J. P. & Neutra, M. R. Epithelial M cells: differentiation and function. Annu. Rev. Cell Dev. Biol. 16, 301–332 (2000).

  8. 8

    McGhee, J. R., Lamm, M. E. & Strober, W. in Mucosal Immunology (eds Ogra, P. et al.) 485–506 (Academic Press, New York, 1999).

  9. 9

    Hein, W. R. in Defense of Mucosal Surfaces: Pathogenesis, immunity and vaccines (eds Kraehenbuhl, J. P. & Neutra, M. R.) 1–16 (Springer-Verlag, Berlin, 1999).

  10. 10

    Bienenstock, J., McDermott, M. R. & Clancy, R. L. in Mucosal Immunology (eds Ogra, P. et al.) 283–292 (Academic Press, New York, 1999).

  11. 11

    O'Leary, A. D. & Sweeney, E. C. Lymphoglandular complexes of the colon: structure and distribution. Histopathology 10, 267–283 (1986).

  12. 12

    Kelsall, B. & 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).

  13. 13

    Kelsall, B. & Strober, W. in Mucosal Immunology (eds Ogra, P. et al.) 293–318 (Academic Press, New York, 1999).

  14. 14

    Butcher, E. & Picker, L. Lymphocyte homing and homeostasis. Science 272, 60–66 (1996).

  15. 15

    Bargatze, R. F., Jutila, M. A. & Butcher, E. C. Distinct roles of L-selectin and integrins α4β7 and LFA-1 in lymphocyte homing to Peyer's patch-HEV in situ: the multistep model confirmed and refined. Immunity 3, 99–108 (1995).

  16. 16

    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).

  17. 17

    Neutra, M. R., Frey, A. & Kraehenbuhl, J. P. Epithelial M cells: Gateways for mucosal infection and immunization. Cell 86, 345–348 (1996).

  18. 18

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

  19. 19

    Owen, R. L. Uptake and transport of intestinal macromolecules and microorganisms by M cells in Peyer's patches–a personal and historical perspective. Semin. Immunol. 11, 157–163 (1999).

  20. 20

    Siebers, A. & Finlay, B. M cells and the pathogenesis of mucosal and systemic infections. Trends Microbiol. 4, 22–29 (1996).

  21. 21

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

  22. 22

    Maury, J., Nicoletti, C., Guzzo-Chambraud, L. & Maroux, S. The filamentous brush border glycocalyx, a mucin-like marker of enterocyte hyper-polarization. Eur. J. Biochem. 228, 323–331 (1995).

  23. 23

    Owen, R. & Bhalla, D. Cytochemical analysis of alkaline phosphatase and esterase activities and of lectin-binding and anionic sites in rat and mouse Peyer's Patch M cells. Am. J. Anat. 168, 199–212 (1983).

  24. 24

    Savidge, T. C. & Smith, M. W. Evidence that membranous (M) cell genesis is immuno-regulated. Adv. Exp. Med. Biol. 371, 239–241 (1995).

  25. 25

    Giannasca, P. J., Giannasca, K. T., Falk, P., Gordon, J. I. & Neutra, M. R. Regional differences in glycoconjugates of intestinal M cells in mice: potential targets for mucosal vaccines. Am. J. Physiol. 267, 1108–1121 (1994).

  26. 26

    Pappo, J. & Owen, R. L. Absence of secretory component expression by epithelial cells overlying rabbit gut-associated lymphoid tissue. Gastroenterology 95, 1173–1174 (1988).

  27. 27

    Gebert, A. & Hach, G. Differential binding of lectins to M cells and enterocytes in the rabbit cecum. Gastroenterology 105, 1350–1361 (1993).

  28. 28

    Giannasca, P. J., Giannasca, K. T., Leichtner, A. M. & Neutra, M. R. Human intestinal M cells display the sialyl Lewis A antigen. Infect. Immun. 67, 946–953 (1999).

  29. 29

    Sharma, R., van Damme, E. J. M., Peumans, W. J., Sarsfield, P. & Schumacher, U. Lectin binding reveals divergent carbohydrate expression in human and mouse Peyer's patches. Histochem. Cell Biol. 105, 459–465 (1996).

  30. 30

    Sierro, F., Pringault, E., Assman, P. S., Kraehenbuhl, J. P. & Debard, N. Transient expression of M-cell phenotype by enterocyte-like cells of the follicle-associated epithelium of mouse Peyer's patches. Gastroenterology 119, 734–743 (2000).

  31. 31

    McClugage, S. G., Low, F. N. & Zimmy, M. L. Porosity of the basement membrane overlying Peyer's patches in rats and monkeys. Gastroenterology 91, 1128–1133 (1986).

  32. 32

    Cook, D. G., Fantini, J., Spitalnik, S. L. & Gonzalez-Scarano, F. Binding of human immunodeficiency virus type I (HIV-1) to galactosylceramide (GalCer):Relationship to the V3 loop. Virology 201, 206–214 (1994).

  33. 33

    Ermak, T. H., Steger, H. J. & Pappo, J. Phenotypically distinct subpopulations of T cells in domes and M-cell pockets of rabbit gut-associated lymphoid tissue. Immunology 71, 530–537 (1990).

  34. 34

    Ermak, T. H., Bhagat, H. R. & Pappo, J. Lymphocyte compartments in antigen-sampling regions of rabbit mucosal lymphoid organs. Am. J. Trop. Med. Hyg. 50, 14–28 (1994).

  35. 35

    Farstad, I. N., Halstensen, T. S., Fausa, O. & Brandtzaeg, P. Heterogeneity of M-cell-associated B and T cells in human Peyer's patches. Immunology 83, 457–464 (1994).

  36. 36

    Bye, W., Allan, C. & Trier, J. Structure, distribution, and origin of M cells in Peyer's patches of mouse Ileum. Gastroenterology 86, 789–801 (1984).

  37. 37

    Neutra, M., Phillips, T., Mayer, E. & Fishkind, D. Transport of membrane-bound macromolecules by M cells in follicle-associated epithelium of rabbit Peyer's patch. Cell Tiss. Res. 247, 537–546 (1987).

  38. 38

    Sicinski, P. et al. Poliovirus type 1 enters the human host through intestinal M cells. Gastroenterology 98, 56–58 (1990).

  39. 39

    Neutra, M. R., Giannasca, P. J., Giannasca, K. T. & Kraehenbuhl, J. P. in Infections of the Gastrointestinal Tract (eds Blaser, M. J., Smith, P. D., Ravdin, J. I., Greenberg, H. B. & Guerrant, R. L.) 163–178 (Raven Press Ltd., New York, 1995).

  40. 40

    Jones, B., Ghori, N. & Falkow, S. Salmonella typhimurium initiated murine infection by penetrating and destroying the specialized epithelial M cells of the Peyer's patches. J. Exp. Med. 180, 15–23 (1994).

  41. 41

    Mantis, N. J., Frey, A. & Neutra, M. R. Accessibility of glycolipid and glycoprotein epitopes on rabbit villus and follicle-associated epitheliaum. Am. J. Physiol. 278, 915–924 (2000).

  42. 42

    Bhalla, D. K. & Owen, R. L. Migration of B and T lymphocytes to M cells in Peyer's patch follicle associated epithelium: An audioradiographic study in mice. Cell. Immunol. 81, 105–117 (1983).

  43. 43

    Ueki, T., Mizuno, M., Ueso, T., Kiso, T. & Tsuji, T. Expression of ICAM-1 on M cells covering isolated lymphoid follicles of the human colon. Acta Med. Okayama 49, 145–151 (1995).

  44. 44

    Huang, G. T. J., Eckmann, L., Savidge, T. & Kagnoff, M. F. Infection of human intestinal epithelial cells with invasive bacteria upregulates apical intercellular adhesion molecule-1 (ICAM-1) expression and neutrophil adhesion. J. Clin. Invest. 98, 572–583 (1996).

  45. 45

    Clark, M. A., Hirst, B. H. & Jepson, M. A. M cell surface β-1 integrin expression and invasin-mediated targeting of Yersinia pseudotuberculosis to mouse Peyer's patch M cells. Infect. Immun. 66, 1237–1243 (1998).

  46. 46

    Marra, A. & Isberg, R. R. Invasin-dependent and invasin-independent pathways for translocatino of Yersinia pseudotubeculosis across Peyer's patch intestinal epithelium. Infect. Immun. 65, 3412–3421 (1997).

  47. 47

    Lelouard, H., Reggio, H., Manget, P., Neutra, M. & Mountcourrier, P. Mucin related epitopes distinguish M cells and enterocytes in rabbit appendix and Peyer's patches. Infect. Immun. 67, 357–367 (1999).

  48. 48

    Neutra, M. R., Mantis, N. J., Frey, A. & Giannasca, P. J. The composition and function of M cell apical membranes: implications for microbial pathogenesis. Semin. Immunol. 11, 171–181 (1999).

  49. 49

    Silvey, K. J., Vajdy, M., Mantis, N. J. & Neutra, M. R. Reovirus: a model to study M cell-specific interactions and secretory antibody function in the intestine. Immunol. Lett. 69, 65 Abstr. 12.9 (1999).

  50. 50

    Roy, M. J. & Varvayanis, M. Development of dome epithelium in gut-associated lymphoid tissues association of IgA with M cells. Cell Tiss. Res. 248, 645–651 (1987).

  51. 51

    Weltzin, R. et al. Binding and transepithelial transport of immunoglobulins by intestinal M cells: demonstration using monoclonal IgA antibodies against enteric viral proteins. J. Cell Biol. 108, 1673–1685 (1989).

  52. 52

    Corthesy, B. et al. A pathogen-specific epitope inserted into recombinant secretory immunoglobulin A is immunogenic by the oral route. J. Biol. Chem. 271, 33670–33677 (1996).

  53. 53

    Zhou, F., Kraehenbuhl, J. P. & Neutra, M. R. Mucosal IgA response to recally administered antigen formulated liposomes in IgA coated liposomes. Vaccine 13, 637–644 (1995).

  54. 54

    Sakamoto, N. et al. A novel Fc receptor for IgA and IgM is expressed on both hematopoietic and non-hematopoietic tissues. Eur. J. Immunol. 31, 1310–1316 (2001).

  55. 55

    Shibuya, A. et al. Fc α/μ receptor mediates endocytosis of IgM-coated microbes. Nature Immunol. 1, 441–446 (2000).

  56. 56

    Allan, C. H. & Trier, J. S. Structure and permeability differ in subepithelial villus and Peyer's patch follicle capillaries. Gastroenterology 100, 1172–1179 (1991).

  57. 57

    Finzi, G. et al. Cathepsin E in follicle associated epithelium of intestine and tonsils: localization to M cells and possible role in antigen processing. Histochemistry 99, 201–211 (1993).

  58. 58

    Phalipon, A. & Sansonetti, P. J. Microbial-host interactions at mucosal sites. Host response to pathogenic bacteria at mucosal sites. Curr. Top. Microbiol. Immunol. 236, 163–189 (1999).

  59. 59

    Andino, R. et al. Engineering poliovirus as a vaccine vector for the expression of diverse antigens. Science 265, 1448–1451 (1994).

  60. 60

    Hantman, M. J., Hohmann, E. L., Murphy, C. G., Knipe, D. M. & Miller, S. I. in Mucosal Immunology (eds Ogra, P. et al.) 779–791 (Academic Press, New York, 1999).

  61. 61

    Iwasaki, A. & Kelsall, B. Unique functions of CD11b+, CD8a+, and double negative Peyer's patch dendritic cells. J. Immunol. 166, 4884–4890 (2001).

  62. 62

    Yamanaka, T. et al. M cell pockets of human Peyer's patches are specialized extensions of germinal centers. Eur. J. Immunol. 31, 107–117 (2001).

  63. 63

    Cepek, K. L. et al. Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the αEβ7 integrin. Nature 372, 190–193 (1994).

  64. 64

    Schon, M. P. et al. Mucosal T lymphocyte numbers are selectively reduced in integrin aE (CD103)-deficient mice. J. Immunol. 162, 6641–6649 (1999).

  65. 65

    Ruedl, C., Rieser, C., Bock, G., Wick, G. & Wolf, H. Phenotypic and functiponal characterization of CD11c+ dendritic cell population in mouse Peyer's patches. Eur. J. Immunol. 26, 1801–1806 (1996).

  66. 66

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

  67. 67

    Maldonado-Lopez, R. et al. CD8α+ and CD8α subclasses of dendritic cells direct the development of distinct T helper cells in vivo. J. Exp. Med. 189, 587–592 (1999).

  68. 68

    Pulendran, B. et al. Distinct dendritic cell subsets differentially regulate the class of immune response in vivo. Proc. Natl Acad. Sci. USA 96, 1036–1041 (1999).

  69. 69

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

  70. 70

    Cook, D. N. et al. CCR6 mediates dendritic cell localization, lymphocyte homeostasis, and immune responses in mucosal tissue. Immunity 12, 495–503 (2000).

  71. 71

    Izadpanah, A., Dwinell, M. B., Eckmann, L., Varki, N. M. & Kagnoff, M. F. Regulated MIP-3α/CCL20 production by human intestinal epithelium: mechanism for modulating mucosal immunity. Am. J. Physiol. 280, 710–719 (2001).

  72. 72

    Sierro, F. et al. Flagellin stimulation of intestinal epithelial cells triggers CCL20-mediated migration of dendritic cells. Proc. Natl Acad. Sci. USA (in the press, 2001).

  73. 73

    Tanaka, Y. et al. Selective expression of liver and activation-regulated chemokine (LARC) in intestinal epithelium in mice and humans. Eur. J. Immunol. 29, 633–642 (1999).

  74. 74

    Hopkins, S. A., Niedergang, F., Corthesy-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, 59–68 (2000).

  75. 75

    Pron, B. et al. Dendritic cells are early cellular targets of Listeria monocytogenes after intestinal delivery and are involved in bacterial spread in the host. Cell. Microbiol. 3, 331–340 (2001).

  76. 76

    Masurier, C. et al. Dendritic cells route human immunodeficiency virus to lymph nodes after vaginal or intravenous administration to mice. J. Virol. 72, 7822–7829 (1998).

  77. 77

    Rescigno, M. et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nature Immunol. 2, 361–367 (2001).

  78. 78

    Macpherson, A. J. et al. IgA production without μ or δ chain expression in developing B cells. Nature Immunol. 2, 625–631 (2001).

  79. 79

    Mowatt, A. M. & Weiner, H. L. in Mucosal Immunology (eds Ogra, P. et al.) 587–618 (Academic Press, New York, 1999).

  80. 80

    Iwasaki, A. & Kelsall, B. L. Mucosal immunity and inflammation. I. Mucosal dendritic cells: their specialized role in initiating T cell responses. Am. J. Physiol. 276, 1074–1078 (1999).

  81. 81

    Kellermann, S. A. & McEvoy, L. M. The peyer's patch microenvironment suppresses T cell responses to chemokines and other stimuli. J. Immunol. 167, 682–690 (2001).

  82. 82

    Gebert, A., Hach, G. & Bartels, H. Co-localization of vimetin and cytokeratins in M cells of rabbit gut-associated lymphoid tissue (GALT). Cell Tiss. Res. 269, 331–340 (1992).

  83. 83

    Debard, N., Sierro, F., Browning, J. & Kraehenbuhl, J. P. Effect of mature lymphocytes and lymphotoxin on the development of the follicle-associated epithelium and M cells in mouse Peyer's patches. Gastroenterology 120, 1173–1182 (2001).

  84. 84

    Gebert, A., Rothkotter, H. J. & Pabst, R. M cells in Peyer's patches of the intestine. Int. Rev. Cytol. 167, 91–159 (1996).

  85. 85

    Gebert, A., Fassbender, S., Werner, K. & Weissferdt, A. The development of M cells in Peyer's patches is restricted to specialized dome-associated crypts. Am. J. Pathol. 154, 1573–1582 (1999).

  86. 86

    Lelouard, H., Sahuquet, A., Reggio, H. & Montcourrier, P. Rabbit M cells and dome enterocytes are distinct cell lineages. J. Cell Sci. 114, 2077–2083 (2001).

  87. 87

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

  88. 88

    Borghesi, C., Taussig, M. J. & Nicoletti, C. Rapid appearance of M cells after microbial challenge is restricted at the periphery of the follicle-associated epithelium of Peyer's patch. Lab. Invest. 79, 1393–1401 (1999).

  89. 89

    Kitamura, D. & Rajewsky, K. Targeted disruption of μ chain membrane exon causes loss of heavy-chain allelic exclusion. Nature 356, 154–156 (1992).

  90. 90

    Chen, J. et al. Immunoglobulin gene rearrangement in B cell deficient mice generated by targeted deletion of the JH locus. Int. Immunol. 5, 647–656 (1993).

  91. 91

    Golovkina, T. V., Shlomchik, M., Hannum, L. & Chervonsky, A. Organogenic role of B lymphocytes in mucosal immunity. Science 286, 1965–1968 (1999).

  92. 92

    Schulte, R. et al. Translocation of Yersinia enterocolitica across reconstituted intestinal epithelial monolayers is triggered by Yersinia invasin binding to β1 integrins apically expressed on M-like cells. Cell. Microbiol. 2, 173–183 (2000).

  93. 93

    Moxey, P. C. & Trier, J. S. Development of villus absorptive cells in the human fetal small intestine: a morphological and morphometric study. Anat. Rec 195, 463–482 (1979).

  94. 94

    Fu, Y. X. & Chaplin, D. D. Development and maturation of secondary lymphoid tissues. Annu. Rev. Immunol. 17, 399–433 (1999).

  95. 95

    Koni, P. A. et al. Distinct roles in lymphoid organogenesis for lymphotoxins α and β revealed in lymphotoxin β-deficient mice. Immunity 6, 491–500 (1997).

  96. 96

    Kuprash, D. V. et al. TNF and lymphotoxin β cooperate in the maintenance of secondary lymphoid tissue microarchitecture but not in the development of lymph nodes. J. Immunol. 163, 6575–6580 (1999).

  97. 97

    Baggiolini, M. Chemokines and leukocyte traffic. Nature 392, 565–568 (1998).

  98. 98

    Kagnoff, M. F. & Eckmann, L. Epithelial cells as sensors for microbial infection. J. Clin. Invest. 100, 6–10 (1997).

  99. 99

    Wurbel, M. A. et al. The chemokine TECK is expressed by thymic and intestinal epithelial cells and attracts double- and single-positive thymocytes expressing the TECK receptor CCR9. Eur. J. Immunol. 30, 262–271 (2000).

  100. 100

    Czerkinsky, C. et al. Mucosal immunity and tolerance: relevance to vaccine development. Immunol. Rev. 170, 197–222 (1999).

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Neutra, M., Mantis, N. & Kraehenbuhl, J. Collaboration of epithelial cells with organized mucosal lymphoid tissues. Nat Immunol 2, 1004–1009 (2001) doi:10.1038/ni1101-1004

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