Abstract
Previous studies support a role for intestinal epithelial cells (IEC) as antigen-presenting cells in mucosal immune responses. T cells activated by IEC are CD8+, suppressor in function, and dependent upon CD8-associated p56lck activation. A 180-kD glycoprotein (gp180) recognized by mAbs B9 and L12 has been identified and shown to be important in CD8+ T cell activation by IEC. Since IEC derived from patients with inflammatory bowel disease (IBD) are incapable of activating CD8+ T cells, we asked whether this correlated with gp180 expression. While frozen sections of normal bowel revealed bright gp180 staining on all IEC, both inflamed and uninflamed ulcerative colitis (UC) specimens showed patchy staining. In Crohn's disease (CD), staining was faint to absent. Flow cytometry confirmed immunohistochemical data. The staining patterns correlated with the ability of IEC to activate CD8-associated p56lck. Normal IEC induced phosphorylation of p56lck in CD8alpha but not CD4+ transfectants. In contrast, both UC and CD IEC activated CD4 and, to a much lesser extent, CD8-associated p56lck. Thus, gp180 expression by IBD IEC appears to be altered, and correlates with a functional alteration of lck activation. This defect may reflect a more proximal event in the pathogenesis of IBD.
Full Text
The Full Text of this article is available as a PDF (553.5 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bland P. W., Warren L. G. Antigen presentation by epithelial cells of the rat small intestine. II. Selective induction of suppressor T cells. Immunology. 1986 May;58(1):9–14. [PMC free article] [PubMed] [Google Scholar]
- Breese E. J., Michie C. A., Nicholls S. W., Murch S. H., Williams C. B., Domizio P., Walker-Smith J. A., MacDonald T. T. Tumor necrosis factor alpha-producing cells in the intestinal mucosa of children with inflammatory bowel disease. Gastroenterology. 1994 Jun;106(6):1455–1466. doi: 10.1016/0016-5085(94)90398-0. [DOI] [PubMed] [Google Scholar]
- Breese E., Braegger C. P., Corrigan C. J., Walker-Smith J. A., MacDonald T. T. Interleukin-2- and interferon-gamma-secreting T cells in normal and diseased human intestinal mucosa. Immunology. 1993 Jan;78(1):127–131. [PMC free article] [PubMed] [Google Scholar]
- Fais S., Pallone F., Squarcia O., Boirivant M., Pozzilli P. T cell early activation antigens expressed by peripheral lymphocytes in Crohn's disease. J Clin Lab Immunol. 1985 Feb;16(2):75–76. [PubMed] [Google Scholar]
- Halstensen T. S., Mollnes T. E., Brandtzaeg P. Persistent complement activation in submucosal blood vessels of active inflammatory bowel disease: immunohistochemical evidence. Gastroenterology. 1989 Jul;97(1):10–19. doi: 10.1016/0016-5085(89)91409-1. [DOI] [PubMed] [Google Scholar]
- Halstensen T. S., Mollnes T. E., Fausa O., Brandtzaeg P. Deposits of terminal complement complex (TCC) in muscularis mucosae and submucosal vessels in ulcerative colitis and Crohn's disease of the colon. Gut. 1989 Mar;30(3):361–366. doi: 10.1136/gut.30.3.361. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Holländer G. A., Simpson S. J., Mizoguchi E., Nichogiannopoulou A., She J., Gutierrez-Ramos J. C., Bhan A. K., Burakoff S. J., Wang B., Terhorst C. Severe colitis in mice with aberrant thymic selection. Immunity. 1995 Jul;3(1):27–38. doi: 10.1016/1074-7613(95)90156-6. [DOI] [PubMed] [Google Scholar]
- Holländer G. A., Wang B., Nichogiannopoulou A., Platenburg P. P., van Ewijk W., Burakoff S. J., Gutierrez-Ramos J. C., Terhorst C. Developmental control point in induction of thymic cortex regulated by a subpopulation of prothymocytes. Nature. 1995 Jan 26;373(6512):350–353. doi: 10.1038/373350a0. [DOI] [PubMed] [Google Scholar]
- Kühn R., Löhler J., Rennick D., Rajewsky K., Müller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993 Oct 22;75(2):263–274. doi: 10.1016/0092-8674(93)80068-p. [DOI] [PubMed] [Google Scholar]
- Li Y., Yio X. Y., Mayer L. Human intestinal epithelial cell-induced CD8+ T cell activation is mediated through CD8 and the activation of CD8-associated p56lck. J Exp Med. 1995 Oct 1;182(4):1079–1088. doi: 10.1084/jem.182.4.1079. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mayer L., Eisenhardt D. Lack of induction of suppressor T cells by intestinal epithelial cells from patients with inflammatory bowel disease. J Clin Invest. 1990 Oct;86(4):1255–1260. doi: 10.1172/JCI114832. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mayer L., Eisenhardt D., Salomon P., Bauer W., Plous R., Piccinini L. Expression of class II molecules on intestinal epithelial cells in humans. Differences between normal and inflammatory bowel disease. Gastroenterology. 1991 Jan;100(1):3–12. doi: 10.1016/0016-5085(91)90575-6. [DOI] [PubMed] [Google Scholar]
- Mayer L., Shlien R. Evidence for function of Ia molecules on gut epithelial cells in man. J Exp Med. 1987 Nov 1;166(5):1471–1483. doi: 10.1084/jem.166.5.1471. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Morrissey P. J., Charrier K., Braddy S., Liggitt D., Watson J. D. CD4+ T cells that express high levels of CD45RB induce wasting disease when transferred into congenic severe combined immunodeficient mice. Disease development is prevented by cotransfer of purified CD4+ T cells. J Exp Med. 1993 Jul 1;178(1):237–244. doi: 10.1084/jem.178.1.237. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mueller C., Knoflach P., Zielinski C. C. T-cell activation in Crohn's disease. Increased levels of soluble interleukin-2 receptor in serum and in supernatants of stimulated peripheral blood mononuclear cells. Gastroenterology. 1990 Mar;98(3):639–646. [PubMed] [Google Scholar]
- Mueller C., Knoflach P., Zielinski C. C. T-cell activation in Crohn's disease. Increased levels of soluble interleukin-2 receptor in serum and in supernatants of stimulated peripheral blood mononuclear cells. Gastroenterology. 1990 Mar;98(3):639–646. [PubMed] [Google Scholar]
- Mullin G. E., Lazenby A. J., Harris M. L., Bayless T. M., James S. P. Increased interleukin-2 messenger RNA in the intestinal mucosal lesions of Crohn's disease but not ulcerative colitis. Gastroenterology. 1992 May;102(5):1620–1627. doi: 10.1016/0016-5085(92)91722-g. [DOI] [PubMed] [Google Scholar]
- Pallone F., Fais S., Squarcia O., Biancone L., Pozzilli P., Boirivant M. Activation of peripheral blood and intestinal lamina propria lymphocytes in Crohn's disease. In vivo state of activation and in vitro response to stimulation as defined by the expression of early activation antigens. Gut. 1987 Jun;28(6):745–753. doi: 10.1136/gut.28.6.745. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Panja A., Barone A., Mayer L. Stimulation of lamina propria lymphocytes by intestinal epithelial cells: evidence for recognition of nonclassical restriction elements. J Exp Med. 1994 Mar 1;179(3):943–950. doi: 10.1084/jem.179.3.943. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Powrie F., Correa-Oliveira R., Mauze S., Coffman R. L. Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cell-mediated immunity. J Exp Med. 1994 Feb 1;179(2):589–600. doi: 10.1084/jem.179.2.589. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Powrie F., Leach M. W., Mauze S., Caddle L. B., Coffman R. L. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int Immunol. 1993 Nov;5(11):1461–1471. doi: 10.1093/intimm/5.11.1461. [DOI] [PubMed] [Google Scholar]
- Powrie F., Leach M. W., Mauze S., Menon S., Caddle L. B., Coffman R. L. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity. 1994 Oct;1(7):553–562. doi: 10.1016/1074-7613(94)90045-0. [DOI] [PubMed] [Google Scholar]
- Raedler A., Fraenkel S., Klose G., Thiele H. G. Elevated numbers of peripheral T cells in inflammatory bowel diseases displaying T9 antigen and Fc alpha receptors. Clin Exp Immunol. 1985 Jun;60(3):518–524. [PMC free article] [PubMed] [Google Scholar]
- Ratnofsky S. E., Peterson A., Greenstein J. L., Burakoff S. J. Expression and function of CD8 in a murine T cell hybridoma. J Exp Med. 1987 Dec 1;166(6):1747–1757. doi: 10.1084/jem.166.6.1747. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rudolphi A., Boll G., Poulsen S. S., Claesson M. H., Reimann J. Gut-homing CD4+ T cell receptor alpha beta+ T cells in the pathogenesis of murine inflammatory bowel disease. Eur J Immunol. 1994 Nov;24(11):2803–2812. doi: 10.1002/eji.1830241134. [DOI] [PubMed] [Google Scholar]
- Sadlack B., Merz H., Schorle H., Schimpl A., Feller A. C., Horak I. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell. 1993 Oct 22;75(2):253–261. doi: 10.1016/0092-8674(93)80067-o. [DOI] [PubMed] [Google Scholar]
- Sartor R. B. Cytokines in intestinal inflammation: pathophysiological and clinical considerations. Gastroenterology. 1994 Feb;106(2):533–539. doi: 10.1016/0016-5085(94)90614-9. [DOI] [PubMed] [Google Scholar]
- Shull M. M., Ormsby I., Kier A. B., Pawlowski S., Diebold R. J., Yin M., Allen R., Sidman C., Proetzel G., Calvin D. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992 Oct 22;359(6397):693–699. doi: 10.1038/359693a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Simpson S. J., Mizoguchi E., Allen D., Bhan A. K., Terhorst C. Evidence that CD4+, but not CD8+ T cells are responsible for murine interleukin-2-deficient colitis. Eur J Immunol. 1995 Sep;25(9):2618–2625. doi: 10.1002/eji.1830250932. [DOI] [PubMed] [Google Scholar]
- Sleckman B. P., Peterson A., Jones W. K., Foran J. A., Greenstein J. L., Seed B., Burakoff S. J. Expression and function of CD4 in a murine T-cell hybridoma. Nature. 1987 Jul 23;328(6128):351–353. doi: 10.1038/328351a0. [DOI] [PubMed] [Google Scholar]
- Strickland R. G., Korsmeyer S., Soltis R. D., Wilson I. D., Williams R. C., Jr Peripheral blood T and B cells in chronic inflammatory bowel disease. Gastroenterology. 1974 Oct;67(4):569–577. [PubMed] [Google Scholar]
- Yio X. Y., Mayer L. Characterization of a 180-kDa intestinal epithelial cell membrane glycoprotein, gp180. A candidate molecule mediating t cell-epithelial cell interactions. J Biol Chem. 1997 May 9;272(19):12786–12792. doi: 10.1074/jbc.272.19.12786. [DOI] [PubMed] [Google Scholar]