Regulatory T cells in the prevention of mucosal inflammatory diseases: patrolling the border

Abstract

Regulatory T (Treg) cells are important contributors to the maintenance of immune tolerance in the periphery, and deficiency of Tregs is associated with various immunopathic diseases. Murine models of autoimmune and autoinflammatory disorders have helped to elucidate how Tregs are involved in these diseases. A feature in common between human and mice that lack one or another of the key Treg subsets is the occurrence of mucosal inflammation. The relatively fragile mucosal surface represents a complex system that is normally well equipped to ward off harmful pathogens yet at the same time is inhibitory to destructive inflammatory responses to biologically needed (probiotic) microorganisms, or other common environmental antigens e.g. nutrients. We here discuss the importance of Tregs in maintaining tolerance at mucosal surfaces and the outcomes of deficiency of Treg function. The intestinal tract and its inflammatory diseases provide the "point of departure" for discussion, but similar considerations could apply to other mucosal linings exposed to the environment such as other members of the digestive system. However, the lungs, bile ducts, urogenital tract and other mucosal surfaces are susceptible to poorly understood inflammatory states that possibly depend on dysfunction of Treg cells. Finally there are now potential therapies predicated on reconstitution of effective function of Treg cells.

Figure 1

Tolerance at a typical mucosal surface where there is constant interaction with the outside environment. There is a requirement for diverse tolerogenic mechanisms to avoid inflammatory responses to non-pathogenic microorganisms/substances. Tolerogenic antigen presenting cells such as dendritic cells (DCs) and macrophages (MΦ), as well as intraepithelial cells (IELs), can promote the induction of regulatory T cells either by the production of suppressive mediators such as TGF-β and IL-10 and/or by cell-cell contact mechanisms. Damaged epithelial cell (ECs) can up-regulate molecules such as α_vβ₆ integrin, which can convert latent TGF-β into the active form. Non-classical MHC molecules can also be expressed on damage EC, where they activate IELs.

Figure 2

FoxP3⁺ regulatory T cell induction and immunotherapy. Examples show current methods of induction (A–D) or depletion (E) in vitro of FoxP3⁺ Tregs for immunotherapy in humans and mice. A) TGF-β mediated induction of FoxP3 expression and uses in prevention of immunopathology in murine disease models. B) Effects of ectopic expression of FoxP3 in murine T cells; a muman example is not available. C) Drug (rapamycin) -mediated induction of FoxP3 Tregs. D) FoxP3 induction by complement receptor stimulation (CD47 ligation) by thrombospondin. E) Deletion of FoxP3 Tregs provides effective anti-tumor therapy in human and murine cancers.