Tracking cellular signatures of type 1 diabetes - moving from blood to peripheral tissues

Type 1 diabetes (T1D) occurs following a breakdown in immunological tolerance resulting in the eventual loss of functional beta cell mass. The natural history of disease includes a high degree of variability in clinical presentation between subjects with T1D. Recent studies in organ donors with T1D highlight a growing appreciation for the variable loss of insulin production within individual islets from those with established T1D. These findings support a model wherein a loss of immune tolerance is regionalized and under checkpoint control.

The factors impacting disease heterogeneity likely include genetic, stochastic, and environmental contributors. Data will be presented from a large cross-sectional cohort of peripheral blood samples assessing the impact of genetic susceptibility alleles on the frequency and phenotype of innate and adaptive immune subsets. We will highlight the impact of age and CMV serostatus on immune phenotypes thought to play an important role in disease pathogenesis. As a model candidate gene, we will present data on the CD226 costimulatory axis and discuss emerging mechanistic data from the NOD on its role in T cell activation. Collectively, the data presented will address a number of sources of disease heterogeneity within the immune system and include integrated studies of peripheral blood, disease-associated tissues, and animal models for functional testing.  This integrated systems approach should help to identify disease endotypes that could benefit from rational targeting of immune checkpoints to restore immune regulation in T1D.