The Immunoreactive Platform of the Pancreatic Islets Influences the Development of Autoreactivity

Abstract

Tissue homeostasis is maintained through a finely tuned balance between the immune system and the organ-resident cells. Disruption of this process not only results in organ dysfunction but also may trigger detrimental autoimmune responses. The islet of Langerhans consists of the insulin-producing β-cells essential for proper control of body metabolism, but less appreciated is that these cells naturally interact with the immune system, forming a platform by which the β-cell products are sensed, processed, and responded to by the local immune cells, particularly the islet-resident macrophages. Although its physiological outcomes are not completely understood, this immunoreactive platform is crucial for precipitating islet autoreactivity in individuals carrying genetic risks, leading to the development of type 1 diabetes. In this Perspective, we summarize recent studies that examine the cross talk between the β-cells and various immune components, with a primary focus on discussing how antigenic information generated during normal β-cell catabolism can be delivered to the resident macrophage and further recognized by the adaptive CD4 T-cell system, a critical step to initiate autoimmune diabetes. The core nature of the islet immune platform can be extrapolated to other endocrine tissues and may represent a common mechanism underlying the development of autoimmune syndromes influencing multiple endocrine organs.

Figure 1

Overview of the islet immune platform and its communication with the lymphoid tissues. The pancreatic β-cells contain two sets of vesicles that provide antigenic materials. The regular insulin DCG mainly contains abundant insulin molecules that are secreted to regulate glucose metabolism. Via the crinophagic pathway, the insulin DCG is fused with lysosomes to degrade the excessive amounts of insulin production, resulting in the generation of a set of denser granules, the crinophagic bodies or crinosomes. This is a physiological process required for maintaining cellular homeostasis but simultaneously generates catabolized insulin fragments that may give rise to the majority of the T-cell responses. The β-cell delivers its immunological information both locally and systemically. First, the β-cell–derived granules are taken up by the islet-resident macrophages that naturally express high levels of MHC-II, resulting in a robust presentation of β-cell antigens. In NOD mice, this process is crucial for proper amplification of the islet-infiltrating T cells. As the autoimmune process moves forward, other APCs, including dendritic cells, may also play a role in presenting islet antigens, an issue not depicted in the figure. Second, the peptide fragments, mostly in the crinosomes, are secreted from the β-cells after glucose challenge. These materials reach various secondary lymphoid tissues and can be recognized by the corresponding T cells. Although divergent T-cell responses could be generated during such peripheral recognition, a representative insulin-reactive T cell acquires an activation phenotype that favors the invasion into the islets and the ability to cause diabetes. TCR, T-cell receptor.

Figure 2

Microscopic studies that reveal the close interactions among the resident macrophages, the vasculatures, and the β-cells in the islets. A: An immunofluorescent image showing the positioning of the islet macrophages (green, labeled by CX₃CR1-GFP) adjacent to the intra-islet vascular structures (red). Note that some macrophages throw their filopodia into the lumen of the blood vessels. Electronic microscopy showing the intimate interactions between the islet macrophages and the β-cells in 4-week-old B6 (B) and NOD (C) mice. The red arrows indicate the insulin DCG taken up as intact by the islet macrophages; the white arrow in C may denote a granule during the passage from the β-cell to the macrophage. Mac, macrophage.