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T cells orchestrate intestinal mucosal shape and integrity

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Abstract

T helper 1-type immune reactions in the gut cause important human diseases, such as Crohn's disease and coeliac disease. Here, Tom MacDonald, Mona Elliott and Sylvia Pender suggest that the tissue injury in these diseases is mediated not by the immune cells, but by cytokine-induced changes in keratinocyte growth factor and matrix metalloproteinase production by resident gut myofibroblasts.

Section snippets

Healthy individuals

In humans, virtually all T cells in the gut epithelium and LP express the αβ T-cell receptor (TCR). LP CD4+ T cells bear all the hallmarks of cells that have been recently activated by antigen. They express CD45R0, CD69, α4β7 and Fas; low levels of L-selectin, HLA-DR and CD25; and a minority are FasL+ (Ref. 1). LP CD4+ T cells are probably derived from T cells activated in the Peyer's patches by lumenal antigens. It is still not clear to what extent intraepithelial lymphocytes (IELs) are

T-cell mediated tissue injury in the gut mucosa often produces mucosal growth as well as ulceration

In the colitis seen in animal models of IBD, a common feature is mucosal thickening (Fig. 2). The colonic mucosa in mice is normally thin with short glands but in IL-2-knockout mice, for example, the mucosa thickens, the glands lengthen and epithelial proliferation is massively increased. Identical changes are seen in the Th1 mucosal response that accompanies colonic infection with the non-invasive pathogen Citrobacter rodentium20, suggesting that the response to the flora in knockout mice

How do activated LP T cells and macrophages cause mucosal injury?

T cells and macrophages producing IFN-γ and TNF-α could increase epithelial renewal by a direct mitogenic effect on epithelial cells. Alternatively, cytokines could affect the production of the growth factors made by gut myofibroblasts, which control epithelial renewal. It has been shown that direct injection of TNF-α or IL-1α can produce mild changes in small intestine shape22, 23. These experiments confirm that cytokines have an effect, but by their nature they cannot address whether the

A hypothesis for regulation of mucosal integrity in immune-mediated diseases of the gut

Here, we propose a model to explain the biochemical and molecular basis for T-cell injury in the intestine that depends on the control of myofibroblast-derived MMPs, TIMPs and epithelial growth factors by cytokines (Fig. 4). Data obtained in the fetal gut model suggest that these molecules are functionally important (and they are expressed at the right time and in the right place in human gastrointestinal disease), but there are major pieces in the jigsaw still missing. Detailed analysis is

Conclusion

We have tried to explain the stereotypic response of the gut to local inflammatory responses. The most important conclusion is that in immune-mediated gut disease, the tissue injury (villous atrophy, crypt hyperplasia and ulceration) is mediated by the myofibroblasts of the LP because their production of epithelial growth factors, MMPs and matrix is dysregulated by cytokines. Furthermore, much of what is considered pathology in the gut, is in fact mucosal growth (i.e. tissue remodelling).

Acknowledgements

The authors thank the Wellcome Trust, BBSRC, Crohn's in Childhood Research Association, and the Special Trustees of St Bartholomew's Hospital for their support, and the late Professor Anne Ferguson for initiating the idea that cell-mediated immune reactions change mucosal shape.

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