Novel epitope begets a novel pathway in type 1 diabetes progression

Abstract

While CD8+ T cells are critical to diabetogenesis in NOD mice, evidence of their involvement in human type 1 diabetes (T1D) has been circumstantial. The existence of CD8+ T cells specific for beta cell peptides has been demonstrated, but functional data regarding the role of these cells in T1D have been lacking. In this issue of the JCI, Skowera et al. describe an unusual self-peptide epitope derived from the leader sequence of preproinsulin (PPI) and show that 50% of HLA-A2+ patients with new-onset T1D possessed circulating CD8+ T cells specific for this epitope, suggesting that PPI plays a critical role in the development of T1D (see the related article beginning on page 3390). They also report that beta cells upregulate PPI expression in the presence of high glucose levels, rendering these cells more susceptible to lysis and potentially accelerating disease. This suggests that interventions aimed at decreasing the PPI-specific CD8+ T cell response early after T1D diagnosis may be efficacious in ameliorating the disease process.

Figure 1. Model for the development of T1D, elucidating the role of PPI-specific CD8⁺ T cells.

This image shows a schematic of an islet before the onset of T1D, with relatively low levels of PPI-derived peptides (as determined in the study in this issue of the JCI by Skowera et al.; ref. 7) expressed on β cells and few or no T cells. Following migration of a dendritic cell to the draining lymph node, both CD4⁺ and CD8⁺ T cells are activated and migrate to the islets. There they encounter PPI-expressing β cells and kill them, resulting in lowered levels of insulin and hyperglycemia, as suggested by Skowera et al. (7). This results in increased PPI production and PPI presentation on both the β cells and resident dendritic cells. This can result in increased sensitivity to killing of β cells by CD8⁺ T cells (7), as well as in local proliferation of the effectors stimulated by resident dendritic cells.