Oral Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

Altered T cell metabolism in type 1 diabetes (#206)

Daniel J Perry 1 , Priya S Lakshmi 1 , Howard R Seay 1 , Lin Zhang 1 , Todd M Brusko 1
  1. University of Florida, Gainesville, FL, United States

Type 1 diabetes (T1D) results from a failure in immune tolerance resulting from multiple genetic susceptibility variants impacting adaptive immunity. Genes within antigen-receptor signaling pathways are highly represented by clusters of variants leading to aberrant activation and downstream signaling. Specifically, upon antigen receptor engagement and costimulation, T cells undergo profound changes from a quiescent to an activated state to support clonal expansion, transcriptional reprogramming, and production of effector molecules. Among these changes is metabolic reprogramming, which is intimately tied to the type of effector response invoked. Prior studies in rodents noted inflammatory responses predominantly utilized glycolysis, whereas memory and regulatory T cells utilized fatty acid oxidation (FAO) for metabolism. We hypothesized that genetic susceptibility variants may alter activation and energy homeostasis in patients with T1D. We developed assays to measure glycolysis and respiration following T cell receptor engagement in healthy controls and patients with T1D in real-time by extracellular flux analysis. Preliminary results indicate that metabolic activation parameters are deficient in T cells from subjects with T1D and from donors carrying the autoimmune risk allele of protein tyrosine phosphatase, non-receptor type 22 (PTPN22). Specifically, patients with T1D and those carrying the susceptible (R620W) PTPN22 genotype exhibited diminished activation-induced oxygen consumption and activation-induced extracellular acidification. Decreases in respiration and glycolysis following activation support the notion that the R620W variant that is encoded by the minor allele is a hypermorph. Further findings suggested donor age and the proportion of naïve to memory T cells dramatically impacted the spare respiratory capacity of T cells, a novel finding that may impact immune development and senescence over time. Taken together, these findings link alterations in immune metabolism to genetic susceptibility, and may reveal novel pathways for restoring immune regulation in T1D.