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

11 - Dendritic cells in the gut and their possible role in disease

from IV - Dendritic cells and immune evasion of bacteria in vivo

Summary

The gut represents the largest lymphoid tissue of the whole body. The delicate task of the intestinal immune system is the discrimination of harmless food antigens and the commensal bacterial flora from harmful pathogens. Under normal physiologic conditions, immune tolerance is induced to non-pathogenic stimuli while effective immune responses are generated toward dangerous pathogens. Thus “decision making” is an important feature of the intestinal immune system. If inappropriate responses are generated, serious inflammation of the small and large intestine may develop. Crohn's disease (CD) and ulcerative colitis are the two prototypes of such inflammatory bowel disease that are believed to develop as a consequence of a disregulated immune response toward harmless antigens. Despite our limited knowledge on the mechanisms of such “decision making” in the gut, recent evidence suggest an important role of intestinal dendritic cells. Dendritic cells (DCs) can be found in large numbers throughout the gastrointestinal tract where they usually build a tight network underlying the epithelium. This chapter will discuss their contribution to the induction of tolerance and immunity in the intestinal immune system as well as a possible role of these DCs in localized immune responses predisposing the terminal ileum for the development of inflammatory bowel disease (IBD).

DENDRITIC CELLS IN THE INTESTINAL IMMUNE SYSTEM: AN OVERVIEW

The intestinal immune system can be functionally separated into an inductive site and an effector site. The prototypic inductive site in the small intestine is the Peyer's patch, a localized lymphoid structure placed within the bowel wall.

REFERENCES
Mowat, A. M. (2003). Anatomical basis of tolerance and immunity to intestinal antigens. Nat. Rev. Immunol. 3, 331–41
Bilsborough, J. and Viney, J. L. (2004). Gastrointestinal dendritic cells play a role in immunity, tolerance, and disease. Gastroenterology 127, 300–9
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
Kelsall, B. L. and Strober, W. (1996). 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, 237–47
Iwasaki, A., and Kelsall, B. L. (2001). Unique functions of Cd11b+, Cd8 alpha+, and double-negative Peyer's patch dendritic cells. J. Immunol. 166, 4884–90
Macpherson, A. J and Uhr, T. (2004). Induction of protective Iga by intestinal dendritic cells carrying commensal bacteria. Science 303, 1662–5
Bilsborough, J., George, T. C., Norment, A., and Viney, J. L. (2003). Mucosal Cd8alpha+ Dc, with a plasmacytoid phenotype, induce differentiation and support function of T cells with regulatory properties. Immunology 108, 481–92
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
Akbari, O., DeKruyff, R. H., and Umetsu, D. T. (2001). Pulmonary dendritic cells producing Il-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
Sato, A., Hashiguchi, M., Toda, E., Iwasaki, A., Hachimura, S., and Kaminogawa, S. (2003). Cd11b+ Peyer's patch dendritic cells secrete Il-6 and induce Iga secretion from naive B cells. J. Immunol. 171, 3684–90
Tsuji, N. M., Mizumachi, K., and Kurisaki, J. (2003). Antigen-specific, Cd4+Cd25+ regulatory T cell clones induced in Peyer's patches. Int. Immunol. 15, 525–34
Hauet-Broere, F., Unger, W. W., Garssen, J., Hoijer, M. A., Kraal, G., and Samsom, J. N. (2003). Functional Cd25− and Cd25+ mucosal regulatory T cells are induced in gut-draining lymphoid tissue within 48 h after oral antigen application. Eur. J. Immunol. 33, 2801–10
Chen, W., Jin, W., Hardegen, N., Lei, K. J., Li, L., Marinos, N., McGrady, G., and Wahl, S. M. (2003). Conversion of peripheral Cd4+Cd25− naive T cells to Cd4+Cd25+ regulatory T cells by Tgf-beta induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–86
Fantini, M. C., Becker, C., Monteleone, G., Pallone, F., Galle, P. R, and Neurath, M. F. (2004). Cutting edge: Tgf-beta induces a regulatory phenotype in Cd4+Cd25− T cells through Foxp3 induction and down-regulation of Smad7. J. Immunol. 172, 5149–53
Gonnella, P. A., Chen, Y., Inobe, J., Komagata, Y., Quartulli, M., and Weiner, H. L. (1998). In situ immune response in gut-associated lymphoid tissue (Galt) following oral antigen in Tcr-transgenic mice. J. Immunol. 160, 4708–18
Jang, M. H., Kweon, M. N., Iwatani, K., Yamamoto, M., Terahara, K., Sasakawa, C., Suzuki, T., Nochi, T., Yokota, Y., Rennert, P. D., Hiroi, T., Tamagawa, H., Iijima, H., Kunisawa, J., Yuki, Y., and Kiyono, H. (2004). Intestinal villous M cells: an antigen entry site in the mucosal epithelium. Proc. Natl Acad. Sci. U S A 101, 6110–15
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
Niess, J. H., Brand, S., Gu, X., Landsman, L., Jung, S., McCormick, B. A., Vyas, J. M., Boes, M., Ploegh, H. L., Fox, J. G., Littman, D. R., and Reinecker, H. C. (2005). Cx3cr1-Mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307, 254–8
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. J. Exp. Med. 191, 435–44
MacPherson, G. G., Jenkins, C. D., Stein, M. J., and Edwards, C. (1995). Endotoxin-mediated dendritic cell release from the intestine. Characterization of released dendritic cells and Tnf dependence. J. Immunol. 154, 1317–22
Roake, J. A., Rao, A. S., Morris, P. J., Larsen, C. P., Hankins, D. F., and Austyn, J. M. (1995). Dendritic cell loss from nonlymphoid tissues after systemic administration of lipopolysaccharide, tumor necrosis factor, and interleukin 1. J. Exp. Med. 181, 2237–47
Bouma, G. and Strober, W. (2003). The immunological and genetic basis of inflammatory bowel disease. Nat. Rev. Immunol. 3, 521–33
Guarner, F. and Malagelada, J. R. (2003). Gut flora in health and disease. Lancet 361, 512–19
Shanahan, F. (2002). Crohn's disease. Lancet 359, 62–9
Swidsinski, A., Ladhoff, A., Pernthaler, A., Swidsinski, S., Loening-Baucke, V., Ortner, M., Weber, J., Hoffmann, U., Schreiber, S., Dietel, M., and Lochs, H. (2002). Mucosal flora in inflammatory bowel disease. Gastroenterology 122, 44–54
Linskens, R. K., Huijsdens, X. W., Savelkoul, P. H., Vandenbroucke-Grauls, C. M., and Meuwissen, S. G. (2001). The bacterial flora in inflammatory bowel disease: current insights in pathogenesis and the influence of antibiotics and probiotics. Scand. J. Gastroenterol. Suppl.29–40
Ogura, Y., Bonen, D. K., Inohara, N., Nicolae, D. L., Chen, F. F., Ramos, R., Britton, H., Moran, T., Karaliuskas, R., Duerr, R. H., Achkar, J. P., Brant, S. R., Bayless, T. M., Kirschner, B. S., Hanauer, S. B., Nunez, G., and Cho, J. H. (2001). A frame shift mutation in Nod2 associated with susceptibility to Crohn's disease. Nature 411, 603–6
Inohara, N., Ogura, Y., Fontalba, A., Gutierrez, O., Pons, F., Crespo, J., Fukase, K., Inamura, S., Kusumoto, S., Hashimoto, M., Foster, S. J., Moran, A. P., Fernandez-Luna, J. L., and Nunez, G. (2003). Host recognition of bacterial muramyl dipeptide mediated through Nod2. Implications for Crohn's disease. J. Biol. Chem. 278, 5509–12
Watanabe, T., Kitani, A., Murray, P. J., and Strober, W. (2004). Nod2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat. Immunol. 5, 800–8
Leach, M. W., Bean, A. G., Mauze, S., Coffman, R. L., and Powrie, F. (1996). Inflammatory bowel disease in C.B-17 Scid mice reconstituted with the Cd45rbhigh subset of Cd4+ T cells. Am. J. Pathol. 148, 1503–15
Powrie, F., Leach, M. W., Mauze, S., Caddle, L. B., and Coffman, R. L. (1993). Phenotypically distinct subsets of Cd4+ T cells induce or protect from chronic intestinal inflammation in C.B-17 Scid mice. Int. Immunol. 5, 1461–71
Leithauser, F., Trobonjaca, Z., Moller, P., and Reimann, J. (2001). Clustering of colonic lamina propria Cd4(+) T cells to subepithelial dendritic cell aggregates precedes the development of colitis in a murine adoptive transfer model. Lab. Invest. 81, 1339–49
Malmstrom, V., Shipton, D., Singh, B., Al-Shamkhani, A., Puklavec, M. J., Barclay, A. N., and Powrie, F. (2001). Cd134l expression on dendritic cells in the mesenteric lymph nodes drives colitis in T cell-restored Scid mice. J. Immunol. 166, 6972–81
Krajina, T., Leithauser, F., Moller, P., Trobonjaca, Z., and Reimann, J. (2003). Colonic lamina propria dendritic cells in mice with Cd4+ T cell-induced colitis. Eur. J. Immunol. 33, 1073–83
Fuss, I. J., Neurath, M., Boirivant, M., Klein, J. S., Motte, C., Strong, S. A., Fiocchi, C., and Strober, W. (1996). Disparate Cd4+ lamina propria (Lp) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease Lp cells manifest increased secretion of Ifn-gamma, whereas ulcerative colitis Lp cells manifest increased secretion of Il-5. J. Immunol. 157, 1261–70
Stuber, E., Strober, W., and Neurath, M. (1996). Blocking the Cd40l–Cd40 interaction in vivo specifically prevents the priming of T helper 1 cells through the inhibition of interleukin 12 secretion. J. Exp. Med. 183, 693–8
Monteleone, G., Biancone, L., Marasco, R., Morrone, G., Marasco, O., Luzza, F., and Pallone, F. (1997). Interleukin 12 is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells. Gastroenterology 112, 1169–78
Neurath, M. F., Fuss, I., Kelsall, B. L., Stuber, E., and Strober, W. (1995). Antibodies to interleukin 12 abrogate established experimental colitis in mice. J. Exp. Med. 182, 1281–90
Simpson, S. J., Shah, S., Comiskey, M., Jong, Y. P., Wang, B., Mizoguchi, E., Bhan, A. K., and Terhorst, C. T. (1998). T cell-mediated pathology in two models of experimental colitis depends predominantly on the interleukin 12/signal transducer and activator of transcription (Stat)-4 pathway, but is not conditional on interferon gamma expression by T cells. J. Exp. Med. 187, 1225–34
Davidson, N. J., Hudak, S. A., Lesley, R. E., Menon, S., Leach, M. W., and Rennick, D. M. (1998). Il-12, but not Ifn-gamma, plays a major role in sustaining the chronic phase of colitis in Il-10-deficient mice. J. Immunol. 161, 3143–9
Wirtz, S., Finotto, S., Kanzler, S., Lohse, A. W., Blessing, M., Lehr, H. A., Galle, P. R., and Neurath, M. F. (1999). Cutting edge: chronic intestinal inflammation in Stat-4 transgenic mice: characterization of disease and adoptive transfer by Tnf- plus Ifn-gamma-producing Cd4+ T cells that respond to bacterial antigens. J. Immunol. 162, 1884–8
Mannon, P. J., Fuss, I. J., Mayer, L., Elson, C. O., Sandborn, W. J., Present, D., Dolin, B., Goodman, N., Groden, C., Hornung, R. L., Quezado, M., Neurath, M. F., Salfeld, J., Veldman, G. M., Schwertschlag, U., Strober, W., and Yang, Z. (2004). Anti-interleukin-12 antibody for active Crohn's disease. N. Engl. J. Med. 351, 2069–79
Oppmann, B., Lesley, R., Blom, B., Timans, J. C., Xu, Y., Hunte, B., Vega, F., Yu, N., Wang, J., Singh, K., Zonin, F., Vaisberg, E., Churakova, T., Liu, M., Gorman, D., Wagner, J., Zurawski, S., Liu, Y., Abrams, J. S., Moore, K. W., Rennick, D., Waal-Malefyt, R., Hannum, C., Bazan, J. F., and Kastelein, R. A. (2000). Novel P19 protein engages Il-12p40 to form a cytokine, Il-23, with biological activities similar as well as distinct from Il-12. Immunity 13, 715–25
Cua, D. J., Sherlock, J., Chen, Y., Murphy, C. A., Joyce, B., Seymour, B., Lucian, L., To, W., Kwan, S., Churakova, T., Zurawski, S., Wiekowski, M., Lira, S. A., Gorman, D., Kastelein, R. A., and Sedgwick, J. D. (2003). Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–8
Murphy, C. A., Langrish, C. L., Chen, Y., Blumenschein, W., McClanahan, T., Kastelein, R. A., Sedgwick, J. D., and Cua, D. J. (2003). Divergent pro- and antiinflammatory roles for Il-23 and Il-12 in joint autoimmune inflammation. J. Exp. Med. 198, 1951–7
Wiekowski, M. T., Leach, M. W., Evans, E. W., Sullivan, L., Chen, S. C., Vassileva, G., Bazan, J. F., Gorman, D. M., Kastelein, R. A., Narula, S., and Lira, S. A. (2001). Ubiquitous transgenic expression of the Il-23 subunit P19 induces multiorgan inflammation, runting, infertility, and premature death. J. Immunol. 166, 7563–70
Stallmach, A., Giese, T., Schmidt, C., Ludwig, B., Mueller-Molaian, I., and Meuer, S. C. (2004). Cytokine/chemokine transcript profiles reflect mucosal inflammation in Crohn's disease. Int. J. Colorectal Dis. 19, 308–15
Schmidt, C., Giese, T., Ludwig, B., Mueller-Molaian, I., Marth, T., Zeuzem, S., Meuer, S. C., and Stallmach, A. (2005). Expression of interleukin-12-related cytokine transcripts in inflammatory bowel disease: elevated interleukin-23p19 and interleukin-27p28 in Crohn's disease but not in ulcerative colitis. Inflamm. Bowel Dis. 11, 16–23
Fujino, S., Andoh, A., Bamba, S., Ogawa, A., Hata, K., Araki, Y., Bamba, T., and Fujiyama, Y. (2003). Increased expression of interleukin 17 in inflammatory bowel disease. Gut 52, 65–70
Nielsen, O. H., Kirman, I., Rudiger, N., Hendel, J., and Vainer, B. (2003). Upregulation of interleukin-12 and -17 in active inflammatory bowel disease. Scand. J. Gastroenterol. 38, 180–5
Parham, C., Chirica, M., Timans, J., Vaisberg, E., Travis, M., Cheung, J., Pflanz, S., Zhang, R., Singh, K. P., Vega, F., To, W., Wagner, J., O'Farrell, A. M., McClanahan, T., Zurawski, S., Hannum, C., Gorman, D., Rennick, D. M., Kastelein, R. A., Waal Malefyt, R., and Moore, K. W. (2002). A receptor for the heterodimeric cytokine Il-23 is composed of Il-12rbeta1 and a novel cytokine receptor subunit, Il-23r. J. Immunol. 168, 5699–708
Eijnden, S. V., Goriely, S., Wit, D., Willems, F., and Goldman, M. (2005). Il-23 up-regulates Il-10 and induces Il-17 synthesis by polyclonally activated naive T cells in human. Eur. J. Immunol. 35, 469–75
Aggarwal, S., Ghilardi, N., Xie, M. H., Sauvage, F. J., and Gurney, A. L. (2003). Interleukin-23 promotes a distinct Cd4 T cell activation state characterized by the production of interleukin-17. J. Biol. Chem. 278, 1910–14
Happel, K. I., Zheng, M., Young, E., Quinton, L. J., Lockhart, E., Ramsay, A. J., Shellito, J. E., Schurr, J. R., Bagby, G. J., Nelson, S., and Kolls, J. K. (2003). Cutting edge: roles of Toll-like receptor 4 and Il-23 in Il-17 expression in response to Klebsiella pneumoniae infection. J. Immunol. 170, 4432–6
Langrish, C. L., Chen, Y., Blumenschein, W. M., Mattson, J., Basham, B., Sedgwick, J. D., McClanahan, T., Kastelein, R. A., and Cua, D. J. (2005). Il-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–40
Kolls, J. K. and Linden, A. (2004). Interleukin-17 family members and inflammation. Immunity 21, 467–76
Fossiez, F., Djossou, O., Chomarat, P., Flores-Romo, L., Ait-Yahia, S., Maat, C., Pin, J. J., Garrone, P., Garcia, E., Saeland, S., Blanchard, D., Gaillard, C., Das Mahapatra, B., Rouvier, E., Golstein, P., Banchereau, J., and Lebecque, S. (1996). T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J. Exp. Med. 183, 2593–603
Jovanovic, D. V., Di Battista, J. A., Martel-Pelletier, J., Jolicoeur, F. C., He, Y., Zhang, M., Mineau, F., and Pelletier, J. P. (1998). Il-17 stimulates the production and expression of proinflammatory cytokines, Il-beta and Tnf-alpha, by human macrophages. J. Immunol. 160, 3513–21
Molet, S., Hamid, Q., Davoine, F., Nutku, E., Taha, R., Page, N., Olivenstein, R., Elias, J., and Chakir, J. (2001). Il-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J. Allergy Clin. Immunol. 108, 430–8
Antonysamy, M. A., Fanslow, W. C., Fu, F., Li, W., Qian, S., Troutt, A. B., and Thomson, A. W. (1999). Evidence for a role of Il-17 in organ allograft rejection: Il-17 promotes the functional differentiation of dendritic cell progenitors. J. Immunol. 162, 577–84
Wu, C. Y., Kirman, J. R., Rotte, M. J., Davey, D. F., Perfetto, S. P., Rhee, E. G., Freidag, B. L., Hill, B. J., Douek, D. C., and Seder, R. A. (2002). Distinct lineages of T(H)1 cells have differential capacities for memory cell generation in vivo. Nat. Immunol. 3, 852–8
Powrie, F., Leach, M. W., Mauze, S., Menon, S., Caddle, L. B., and Coffman, R. L. (1994). Inhibition of Th1 responses prevents inflammatory bowel disease in Scid mice reconstituted with Cd45rbhi Cd4+ T cells. Immunity 1, 553–62
Ito, H. and Fathman, C. G. (1997). Cd45rbhigh Cd4+ T cells from Ifn-gamma knockout mice do not induce wasting disease. J. Autoimmun. 10, 455–9
Bregenholt, S., Brimnes, J., Nissen, M. H., and Claesson, M. H. (1999). In vitro activated Cd4+ T cells from interferon-gamma (Ifn-gamma)-deficient mice induce intestinal inflammation in immunodeficient hosts. Clin. Exp. Immunol. 118, 228–34
Berg, D. J., Davidson, N., Kuhn, R., Muller, W., Menon, S., Holland, G., Thompson-Snipes, L., Leach, M. W., and Rennick, D. (1996). Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and Cd4(+) Th1-like responses. J. Clin. Invest. 98, 1010–20
Pflanz, S., Timans, J. C., Cheung, J., Rosales, R., Kanzler, H., Gilbert, J., Hibbert, L., Churakova, T., Travis, M., Vaisberg, E., Blumenschein, W. M., Mattson, J. D., Wagner, J. L., To, W., Zurawski, S., McClanahan, T. K., Gorman, D. M., Bazan, J. F., Waal Malefyt, R., Rennick, D., and Kastelein, R. A. (2002). Il-27, a heterodimeric cytokine composed of Ebi3 and P28 protein, induces proliferation of naive Cd4(+) T cells. Immunity 16, 779–90
Lucas, S., Ghilardi, N., Li, J., and Sauvage, F. J. (2003). Il-27 regulates Il-12 responsiveness of naive Cd4+ T cells through Stat1-dependent and -independent mechanisms. Proc. Natl Acad. Sci. U S A 100, 15047–52
Takeda, A., Hamano, S., Yamanaka, A., Hanada, T., Ishibashi, T., Mak, T. W., Yoshimura, A., and Yoshida, H. (2003). Cutting edge: role of Il-27/Wsx-1 signaling for induction of T-Bet through activation of Stat1 during initial Th1 commitment. J. Immunol. 170, 4886–90
Nieuwenhuis, E. E., Neurath, M. F., Corazza, N., Iijima, H., Trgovcich, J., Wirtz, S., Glickman, J., Bailey, D., Yoshida, M., Galle, P. R., Kronenberg, M., Birkenbach, M., and Blumberg, R. S. (2002). Disruption of T helper 2-immune responses in Epstein–Barr virus-induced gene 3-deficient mice. Proc. Natl Acad. Sci. U S A 99, 16951–6
Wang, J. and Fu, Y. X. (2005). Tumor necrosis factor family members and inflammatory bowel disease. Immunol. Rev. 204, 144–55
Atreya, R., Mudter, J., Finotto, S., Mullberg, J., Jostock, T., Wirtz, S., Schutz, M., Bartsch, B., Holtmann, M., Becker, C., Strand, D., Czaja, J., Schlaak, J. F., Lehr, H. A., Autschbach, F., Schurmann, G., Nishimoto, N., Yoshizaki, K., Ito, H., Kishimoto, T., Galle, P. R., Rose-John, S., and Neurath, M. F. (2000). Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in Crohn's disease and experimental colitis in vivo. Nat. Med. 6, 583–8
Strober, W., Fuss, I. J., and Blumberg, R. S. (2002). The immunology of mucosal models of inflammation. Annu. Rev. Immunol. 20, 495–549
Yamanaka, T., Helgeland, L., Farstad, I. N., Fukushima, H., Midtvedt, T., and Brandtzaeg, P. (2003). Microbial colonization drives lymphocyte accumulation and differentiation in the follicle-associated epithelium of Peyer's patches. J. Immunol. 170, 816–22
Onderdonk, A. B., Richardson, J. A., Hammer, R. E., and Taurog, J. D. (1998). Correlation of cecal microflora of Hla-B27 transgenic rats with inflammatory bowel disease. Infect. Immun. 66, 6022–3
Rath, H. C., Ikeda, J. S., Linde, H. J., Scholmerich, J., Wilson, K. H., and Sartor, R. B. (1999). Varying cecal bacterial loads influences colitis and gastritis in Hla-B27 transgenic rats. Gastroenterology 116, 310–19
Mizoguchi, A., Mizoguchi, E., Chiba, C., and Bhan, A. K. (1996). Role of appendix in the development of inflammatory bowel disease in Tcr-alpha mutant mice. J. Exp. Med. 184, 707–15
May, E., Lambert, C., Holtmeier, W., Hennemann, A., Zeitz, M., and Duchmann, R. (2002). Regional variation of the alphabeta T cell repertoire in the colon of healthy individuals and patients with Crohn's disease. Hum. Immunol. 63, 467–80
Kuckelkorn, U., Ruppert, T., Strehl, B., Jungblut, P. R., Zimny-Arndt, U., Lamer, S., Prinz, I., Drung, I., Kloetzel, P. M., Kaufmann, S. H., and Steinhoff, U. (2002). Link between organ-specific antigen processing by 20s proteasomes and Cd8(+) T cell-mediated autoimmunity. J. Exp. Med. 195, 983–90
Becker, C., Wirtz, S., Blessing, M., Pirhonen, J., Strand, D., Bechthold, O., Frick, J., Galle, P. R., Autenrieth, I., and Neurath, M. F. (2003). Constitutive P40 promoter activation and Il-23 production in the terminal ileum mediated by dendritic cells. J. Clin. Invest. 112, 693–706