Regulatory T cells are abundant in GALT and prevent inflammatory reactions against intestinal commensal microbes. It is estimated that the proportion of FOXP3+ Tregs among CD4+ cells is about twofold greater in the intestine than in other tis sues. Many of these Tregs are induced in the gut in response to antigens encountered locally and thus belong to the category of peripheral Tregs (see Fig. 1). The factors that contribute to the generation of these peripheral Tregs include local production of retinoic acid and TGF-β by CD103+ DCs and lamina propria macrophages. Both retinoic acid and TGF-β promote FOXP3 expression and inhibit the generation of Th1 and Th2 cells. Furthermore, fermentation metabolites, such as the short-chain fatty acid butyrate produced by intestinal com mensal bacteria, especially Clostridia species, stimulate peripheral expansion of Tregs. As discussed in Chapter 15, Tregs are thought to suppress immune responses by several mechanisms. Of these, the dominant mechanism in the gut seems to be pro duction of the immunosuppressive cytokine IL-10.
Fig1. Effector and regulatory T cells in the intestinal mucosa. Th17 effector T cells and regulatory T cells are abundant in the intestinal mucosa. Bacterial antigen–specific Th17 cells differentiate from naive CD4+ T cells in gut-associated lymphoid tissues (not shown) in response to antigens presented by dendritic cells (DCs) and cytokines they secrete, including interleukin-6 (IL-6) and IL-23. Differentiation of bacterial anti gen–specific regulatory T cells (Tregs) is promoted by transforming growth factor-β (TGF-β) and retinoic acid produced by intestinal epithelial cells. Thymic Tregs that migrate to the intestine expand in number under the influence of bacterial metabolites. Regulatory T cells require antigen presentation by DCs (not shown); the nature of these antigens is unknown.
Several cytokines, including TGF-β, IL-10, and IL-2, play crucial roles in maintaining homeostasis in the gut immune system, and deficiencies in these cytokines or their receptors result in pathologic bowel inflammation. Much of our knowledge of cytokine-mediated regulation in the gut comes from studies with cytokine or cytokine receptor gene knockout mice. A major feature of the phenotype of mice with engineered deficiencies in TGF-β, IL-10, IL-10 receptor, IL-2, and the IL-2 receptor is uncontrolled inflammation in the bowel. Mutations in the IL-10 receptor gene also cause a rare monogenic type of colitis in infants, called very early onset inflammatory bowel disease (VEO-IBD), confirming the importance of IL-10 in preventing pathologic intestinal inflammation in humans. The uncontrolled inflammation observed in the gut in the absence of these cytokines or their receptors is most likely caused by immune responses to commensal gut flora because the inflammation does not occur in mice raised in germ-free conditions.
The cellular sources of the cytokines and the relevant receptor-expressing target cells that are critical for preventing bowel inflammation are not completely defined. Mouse models in which cytokines, cytokine receptors, and cytokine receptor signaling are genetically ablated only in specific cell types have been used to address the question of which cell types are important. In the case of TGF-β-dependent and IL-10-dependent regulation of gut inflammation, evidence indicates that Tregs are an important source of these cytokines. For example, selective deletion of the IL-10 gene in FOXP3+ cells leads to severe colitis, consistent with the critical role of Treg-produced IL-10 in maintaining homeostasis in the gastrointestinal tract. The target cells that express receptors for and are regulated by TGF-β and IL-10 likely include DCs, effector T cells, innate effector cells such as macrophages, and epithelial cells. IBD in mice lacking IL-2 or its receptor is a consequence of defects in the development and function of Tregs, which require IL-2 for their maintenance.
