Gastroenterology

Gastroenterology

Volume 127, Issue 1, July 2004, Pages 300-309
Gastroenterology

Special reports and reviews
Gastrointestinal dendritic cells play a role in immunity, tolerance, and disease

https://doi.org/10.1053/j.gastro.2004.01.028Get rights and content

Abstract

Discrimination between beneficial commensal organisms and potentially harmful pathogens is a central component of the essential role that gut immune cells play in maintaining the balance between immune activation and tolerance. Antigen presenting cells (APC) are the key to this process, and the type of APC, including epithelial cells, B cells, macrophages, and dendritic cells (DC), in the gut is varied. The purpose of this review is to focus on the vast amount of data that has recently been generated on gastrointestinal dendritic cells in the context of their potential function and contribution to mucosal immunity, tolerance, and disease.

Section snippets

DC populations and their location in the gastrointestinal tract

In an attempt to generate a comprehensive review of the current literature relevant to the function of the immune system in the gastrointestinal tract, we focus on studies that have involved DC isolated from the gut, as opposed to those studies of DC from other tissue origins (i.e., spleen and peripheral lymph nodes [PLN]), because it is increasingly evident that the tissue microenvironment, among other factors, can significantly influence DC responses to stimulation.

The phenotypic analysis of

Antigen uptake by DC in the GI tract

The organization of the mucosal immune system has been elegantly reviewed elsewhere5 and can be roughly divided into organized lymphoid tissues (including Peyer’s patches and MLN) and generalized or diffuse tissues interspersed with effector cells of the immune system (lamina propria and intestinal epithelium). Traditionally, Peyer’s patches have been studied as the main site for induction of mucosal immunity, given their intimate localization with the intestinal lumen, the presence of B-cell

Migration of DC in the GI tract

DC migration is an important attribute for the ability of DC to control and disseminate an immune response, and a number of key studies have highlighted the diversity in chemokine responsiveness by different DC populations located in the same intestinal tissues. Because DC migration is thought to be largely under the control of chemokines and chemokine receptors, it is informative to determine chemokine receptor expression and reactivity to chemokines by different GI DC populations in vitro and

GI DC contribution to immunity

Engagement of the members of the TNFR family on DC is a well-published methodology to enhance DC immunostimulatory function. However, DC isolated from GI tissues can exhibit different responses to such stimuli. Engagement of RANK on DC by RANKL that is usually expressed on activated T cells has been shown to stimulate the secretion of cytokines such as IL-1, IL-6, and IL-12 by splenic DCs but appears to induce IL-10 transcription in Peyer’s patch DC.49 It is tempting to speculate, therefore,

GI DC contribution to tolerance

Potential mechanisms underlying tolerance in the GI tract have been thoroughly reviewed elsewhere.54 In this section of the review, we will highlight some of the major points, with particular focus on the role of DC in tolerance under steady-state conditions and tolerance induced following oral administration of protein. The potential mechanisms for oral tolerance induction have included functional T-cell anergy/deletion or induction of regulatory T cells that produce TGF-β (Th3) or IL-10

GI DC contribution to disease

Animal model systems of colitis have been used extensively in an effort to determine the possible mechanisms that contribute to the initiation of colitis in humans.74 One model in particular has been very well characterized and involves the transfer of CD45RB high CD4+ T cells to SCID mice, which leads to the development of chronic colitis with intestinal pathology similar to that seen for IBD in humans.75 Studies focusing on the early events of this model implicated a role for DC in the

Conclusion

When discussing the role of DC and DC subsets in the intestinal immune system, we should make a cautionary note. The influence of a variety of different parameters, including antigen dose; T-cell cross-talk; local cytokine, chemokine, or metabolite production; signals through pathogen interactions; and local tissue microenvironment, just to name a few, are likely to have the ability to influence the outcome of T-cell priming by DC populations. Thus, it is increasingly obvious that we must

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    Dr. Bilsborough’s current address is: Zymogenetics, 1201 Eastlake Avenue E, Seattle, Washington 98102.

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