Trends in Immunology
ReviewIntestinal CD103+ dendritic cells: master regulators of tolerance?
Section snippets
Tolerance versus immunity in the intestine – a delicate balancing act
The intestinal immune system must discriminate between pathogens and harmless antigens such as commensal microorganisms and dietary constituents. In the case of pathogens and other harmful antigens, it is necessary to induce a strong and protective response, resulting in the elimination of the threat. However, the usual response to harmless antigens or nutrients is to induce tolerance 1, 2, which prevents unnecessary inflammation and hypersensitivity. This state of hyporesponsiveness to fed
DCs in the intestine
DCs can be found in all the lymphoid organs associated with the intestine such as PPs, isolated lymphoid follicles (ILFs) and MLNs, as well as scattered throughout the subepithelial LP of both the small intestine and colon 9, 16, 17. Several DC populations have been described in the organised tissues of PPs and MLNs (see Table 1 and [18] for review), but recently it has become apparent that the DCs in the mucosa itself play a crucial role in directing immune responses to luminal antigens 16, 19
CD103+ DCs in the LP
CD103 (αE integrin), which binds the integrin β7 to form the αEβ7 complex, was first detected as a marker of intraepithelial CD8+ T cells in the gut 25, 26, but its function remains unclear. Its best-known ligand, E-cadherin is expressed by intestinal epithelial cells (IECs) and is suggested to function in maintaining CD103+ T cells and CD103+ DCs in the intestine 26, 27, 28. However, to the best of our knowledge, this has yet to be proven. An additional, uncharacterised ligand for CD103 has
Functions of LP DCs in resting intestine
CD103+ LP DCs have several unique features that distinguish them from other DCs. The first documented of these is the ability to imprint the expression of the gut homing markers CCR9 and α4β7 on interacting naïve T and B cells and to induce expression of FoxP3 by naïve CD4+ T cells 22, 44, 45, 46. This occurs in the MLNs rather than in the mucosa itself, where naïve T lymphocytes are rare 47, 48. Although CD103+ DCs appear to be the only cells that can present intestinal protein or bacterial
Conditioning of physiological properties on mucosal DCs
The studies discussed so far indicate that CD103+ DCs are crucial for gut homeostasis, but how they acquire their unique tolerogenic and imprinting properties is not yet fully understood. Although it remains possible that there could be specific precursors that replenish the CD103+ population, most evidence suggests that this is achieved by a local conditioning effect on DC precursors after they arrive in the mucosa. A number of such factors have been identified, including luminal bacteria,
Mucosal DCs and active immune responses
Thus far, we have focussed on CD103+ DCs as the lynchpin of tolerance under steady state conditions, and a paradigm has evolved that they might be inherently tolerogenic in nature [1]. By contrast, the antigen-presenting cells (APCs) involved in the induction of protective immunity or inflammatory reactions in the gut have not yet been identified precisely. Several groups have proposed that such responses might involve a distinct population of CD103– DCs that are hard-wired to drive effector T
Concluding remarks
The special properties of CD103+ DCs and the likelihood that local factors determine their functions make these attractive targets for manipulating the intestinal immune response. In particular, if these DCs are inherently tolerogenic, it is tempting to propose that this could be exploited to reverse inflammatory diseases and food allergies, perhaps by delivery of specific antigen to CD103+ DCs. Alternatively, if specific intrinsic or environmental mediators underlying the tolerogenic
Acknowledgements
The work of the authors is supported by the Wellcome Trust UK.
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These authors contributed equally.