Essential immunologic orchestrators of intestinal homeostasis

Abstract

Over the past 25 years, substantial advances have been made in our understanding of the cellular and molecular pathways that are essential to maintain a state of health in the mammalian gastrointestinal tract, an organ that is densely colonized by both immune cells and trillions of microbes. Seminal studies in the 1990s identified that several cytokines, antigen-presentation molecules, and components of the T cell receptor were necessary to prevent the development of spontaneous intestinal inflammation in mice. Subsequent research revealed that these pathways orchestrate beneficial interactions with intestinal microbes, involve complex communication between innate and adaptive immune cells, and can be dysregulated in human inflammatory bowel disease. Here, we discuss how these early findings set the stage for numerous other advances and shaped our current knowledge of host-microbiota interactions and intestinal homeostasis in mammals. It is expected that continued investigation of these areas will define previously unknown immunologic mechanisms of tolerance and inflammation in the intestine that can be exploited to benefit human health.

Figure 1.. IL-10-dependent regulation of intestinal health.

T cells, especially Treg cells, are the critical cellular source of IL-10 in the mammalian intestine. The gut microbiota is critical for the induction of intestinal Treg cells and IL-10 production. B. fragilis–derived PSA acts on DCs, resulting in IL-10 expression. In addition, bacteria-stimulated macrophage can also directly secrete IL-10 and support Treg cell development. Thus, DC-derived IL-10 binds to IL-10R expressed on Treg cells, which induces STAT3 activation and the expression of abundant IL-10. IL-10 limits TH1 and TH17 cell differentiation through inhibition of IL-12 and IL-23, respectively. Treg-derived IL-10 drives macrophages to execute tolerogenic functions and maintain intestinal homeostasis. In addition, IL-10 regulates cellular metabolism in macrophages by suppressing mTOR activity, thus reducing glucose uptake and glycolysis while promoting oxidative phosphorylation. Essential pathways that prevent spontaneous inflammation are highlighted in red.

Figure 2.. IL-2-dependent regulation of intestinal health.

During intestinal homeostasis, IL-2 is produced by activated CD4⁺ T cells, DCs, and other unknown cells. IL-2 is mainly consumed by regulatory T cells and activated CD4⁺ T cells. It is now widely appreciated that IL-2 promotes the differentiation of TH1 cells, TH2 cells, and Treg cells while inhibiting TH17 cells. Moreover, Treg cells efficiently sequester IL-2 from effector T cells and use it to maintain high levels of CD25 and Foxp3 expression, enhancing its suppressive capacity. Essential pathways that prevent spontaneous inflammation are highlighted in red.

Figure 3.. Roles for antigen-presentation in regulating intestinal homeostasis.

Microbiota are sampled by intestinal Zbtb46⁺ conventional DCs (cDCs), and bacteria-loaded cDCs then migrate to the draining mesenteric lymph nodes and activate naïve CD4⁺ T cells by presenting commensal bacteria–derived antigen via MHC-II, resulting in the differentiation of effector and regulatory microbiota–specific CD4⁺ T cells. MHC-II⁺ RORγt⁺ ILC3s contact antigen-experienced T effector cells, resulting in deletion of commensal bacteria–specific CD4⁺ effector T cells, a process termed intestinal selection. In addition, activated CD4⁺ T cells partly differentiate into Treg cells, which migrate to lamina propria and regulate intestinal homeostasis. Essential pathways that prevent spontaneous inflammation are highlighted in red.

Fig. 4.. Current and potential therapeutic targets in IBD.

A number of current and potential future targets exist to provide therapeutic benefit in the context of IBD. These targets influence the generation, maintenance, or effector function of innate and adaptive immune cells. Symbol definitions: ❖, efficacy exhibited in clinical trials; *, FDA-approved and providing clinical benefit; #, promising preclinical target in mouse models; ✧, failed or poor efficacy in clinical trials.