The Mucosal Immune System and Its Regulation by Autophagy

Abstract

The gastrointestinal tract presents a unique challenge to the mucosal immune system, which has to constantly monitor the vast surface for the presence of pathogens, while at the same time maintaining tolerance to beneficial or innocuous antigens. In the intestinal mucosa, specialized innate and adaptive immune components participate in directing appropriate immune responses toward these diverse challenges. Recent studies provide compelling evidence that the process of autophagy influences several aspects of mucosal immune responses. Initially described as a "self-eating" survival pathway that enables nutrient recycling during starvation, autophagy has now been connected to multiple cellular responses, including several aspects of immunity. Initial links between autophagy and host immunity came from the observations that autophagy can target intracellular bacteria for degradation. However, subsequent studies indicated that autophagy plays a much broader role in immune responses, as it can impact antigen processing, thymic selection, lymphocyte homeostasis, and the regulation of immunoglobulin and cytokine secretion. In this review, we provide a comprehensive overview of mucosal immune cells and discuss how autophagy influences many aspects of their physiology and function. We focus on cell type-specific roles of autophagy in the gut, with a particular emphasis on the effects of autophagy on the intestinal T cell compartment. We also provide a perspective on how manipulation of autophagy may potentially be used to treat mucosal inflammatory disorders.

Keywords: ATG16L1; IBD; Treg cells; autophagy; colitis; inflammasome; intestinal epithelial cells; metabolism.

Figure 1

The colonic mucosa. The epithelial cell layer of the intestinal mucosa separates the luminal content harboring the microflora (green) from the underlying lamina propria. Specialized secretory epithelial cells, termed goblet cells, produce and secrete mucus to enforce the barrier (red). Cell nuclei are stained in blue.

Figure 2

The autophagy pathway. Autophagosome formation is a stepwise process characterized by dynamic remodeling of cytoplasmic membranes. Proteins that control activation, elongation, and completion of an autophagosome are grouped into five functional complexes that are active at different stages of the autophagy pathway.

Figure 3

Cell-specific functions of autophagy in the intestinal mucosa. Autophagy pathway is essential for several key functions of distinct cell types that promote intestinal immune homeostasis. Perturbation in the autophagy pathway results in decreased antibacterial defense in IECs and MPs. Autophagy also facilitates secretory functions of Paneth cells and goblet cells, is involved in antigen presentation by DC, and limits proinflammatory cytokine production from MP. Furthermore, defects in autophagy pathway strongly compromise the survival of particular subsets of T cells and B cells.

Figure 4

Autophagy regulates inflammasome-associated cytokine responses. Autophagy negatively regulates production of proinflammatory IL-1β in MPs through several mechanisms, indirectly through degradation of damaged mitochondria (mitophagy) to limit ROS production, and directly through degradation of inflammasome complexes and pro-IL-1β. Autophagy may also positively regulate IL-1β by mediating its unconventional extracellular secretion.

Figure 5

Defective autophagy alters the balance of the intestinal CD4⁺ T cell subsets. T cell-specific ablation of autophagy results in a strong decrease in the numbers of Treg cells and also reductions in Th1 and Th17 effector cells. Conversely, loss of autophagy promotes expansion of intestinal Th2 cells, leading to aberrant responses to luminal antigens and subsequent intestinal pathology. Ag - antigen.

Figure 6

Differential reliance on autophagy within intestinal T cell subsets corresponds to their different metabolic profiles. Cell-intrinsic defects in autophagy negatively affect T cell subsets, with the exception of Th2 cells. Treg cells and memory CD8⁺ T cells, which rely on lipid metabolism for survival, were shown to be the most sensitive to autophagy perturbation. However, the role of autophagy CD4⁺ memory T cells formation has not yet been investigated.