Islet beta-cells and intercellular adhesion molecule-1 (ICAM-1): Integrating immune responses that influence autoimmunity and graft rejection

Abstract

Type 1 diabetes (T1D) develops due to autoimmune targeting of the pancreatic islet β-cells. Clinical symptoms arise from reduced insulin in circulation. The molecular events and interactions between discrete immune cell populations, infiltration of such leukocytes into pancreatic and islet tissue, and selective targeting of the islet β-cells during autoimmunity and graft rejection are not entirely understood. One protein central to antigen presentation, priming of immune cells, trafficking of leukocytes, and vital for leukocyte effector function is the intercellular adhesion molecule-1 (ICAM-1). The gene encoding ICAM-1 is transcriptionally regulated and rapidly responsive (i.e., within hours) to pro-inflammatory cytokines. ICAM-1 is a transmembrane protein that can be glycosylated; its presence on the cell surface provides co-stimulatory functions for immune cell activation and stabilization of cell-cell contacts. ICAM-1 interacts with the β2-integrins, CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1), which are present on discrete immune cell populations. A whole-body ICAM-1 deletion protects NOD mice from diabetes onset, strongly implicating this protein in autoimmune responses. Since several different cell types express ICAM-1, its biology is fundamentally essential for various physiological and pathological outcomes. Herein, we review the role of ICAM-1 during both autoimmunity and islet graft rejection to understand the mechanism(s) leading to islet β-cell death and dysfunction that results in insufficient circulating quantities of insulin to control glucose homeostasis.

Keywords: Autoimmunity; ICAM-1; Inflammation; Pancreatic islet; Type 1 diabetes.

Figure 1.. ICAM-1 is involved at multiple levels and in cell types in autoimmunity.

A. Antigen presenting cells (APC) use ICAM-1 interactions with LFA-1 on T-cells as a secondary signal to facilitate priming and activation responses. B. The islet beta-cell (purple) responds to variety of cytokines, including interleukin-1β (IL-1β; e.g., from macrophages) and interferon-gamma (IFNγ; e.g., from T-cells). IL-1β signals through the transcriptional factor p65 while IFN-γ activates STAT1 to control gene expression in islet β-cells. As examples, Icam1 and selected genes that encode chemokines are responsive to cytokines via p65/STAT1 activatsion. Chemokines are secreted proteins that recruit immune cells to a site of inflammation. Islet beta-cells increase ICAM-1 abundance to promote interaction with LFA-1. This ICAM-1/LFA-1 interaction could facilitate direct contact with effector T-cells (shown in red) in the islet. Collectively, these events are help explain some of the events driving the autoimmune process that ultimately leads to T1D. This figure was generated using BioRender.

Figure 2.. Three major compartments where ICAM-1 influences immune cell activity.

Three possiblities for ICAM-1 to influence autoimmunity include: 1) priming of T-cells (left panel), 2) trafficking of immune cells (middle panel), and 3) effector function (right panel). While ICAM-1 likely performs these roles as part of healthy immune cell activity, each of these processes may contribute to ICAM-1 dependent events that lead to islet beta-cell loss during autoimmunity and islet graft rejection. This figure was generated using BioRender.