Antigen presentation events in autoimmune diabetes

Abstract

Antigen presenting cells (APC) be they dendritic cells (DC) or macrophages reside in all tissues. Their role varies from presenting antigen, clearing the tissue from unwanted material, helping in the remodeling that follows injury and inflammation, to a supporting or trophic function. Their features, biology, and turnover may be unique for each organ, modulated by the particular anatomy and physiology of the tissue. These features affect the handling and presentation of antigens, either exogenous such as those from viruses or bacteria, or endogenous, autologous proteins in situations of autoimmunity. Herein, we focus on the resident APC of the islets of Langerhans and their role in autoimmune diabetes. The intra-islet APC are central cells in diabetogenesis by presenting beta cell derived antigens and by modulating the localization of T cells into the islets.

Figure 1. Islet size and DC content in normal and in CSF-1-/- mice (Op/Op)

(a) Distribution of islet area vs. CD11c+ cells in islets of 6 week old C57BL/6 mice. (b) Comparison of islet CD11c+ content in islets of C57BL/6 and Op/Op mice. (c) Distribution of islet area vs. CD11c+ cells in islets of 6 week old Op/Op mice. From reference .

Figure 2. Islet DC present β-cell derived antigen to specific T cell hybridomas

(a and b) Electron microscopy analysis of NOD.Rag-1^-/- islets showing islet DC with an insulin granule inside a vacuole (arrow) (a) and islet DC with dendrites extending to adjacent β-cells (b). (c to e) Dispersed islet T cell assays showing: insulin-specific T cell hybridomas cultured with titrating amounts of NOD.Rag-1^-/- dispersed islets (c), 3A9 T cell hybridomas cultured with dispersed islets from high producer IP-HEL mice (ILK3 strain) (d) or cultured with dispersed islets from low producer IP-HEL mice (117 strain) with or without low dose STZ treatment 4 days before islet isolation. Panel (a), (c), (d) and (e) published as Figure 3 and 6 from reference , with permission from PNAS. Panel (b) is from unpublished data.

Figure 3. Proposed model of CD4 T cell entry into the islets of Langerhans Specific T cell entry

(a) Secretory granules are taken up by the islet DC (shown in green), which are then processed and its peptides presented by MHC II. (b) Specific CD4 T cells (shown in blue) encounter their antigen presented by islet DC protruding through the fenestrated endothelium of the vessel. (c) MHC II recognition and the interaction of LFA-1/ICAM-1 favors the retention and adhesion to the endothelium of the specific T cell in the vessel. (d) The retention allows the entry of the T cell into the islet. Once inside the islet, T cell interacts with islet DC and become activated. These steps will trigger inflammatory signals and gene changes in the islet increasing ICAM-1, VCAM-1 and inflammatory chemokines. Non-specific T cell entry: (e) Non-specific T cells in circulation (shown in red) will encounter the inflammatory signals (chemokines and VCAM-1) that will allow its retention and adhesion to the islet endothelium. (f and g) Attachment to VCAM-1 and the inflammatory chemokine gradient will lead to non-specific T cell entry into the islet.