Peripheral autoreactive CD8 T-cell frequencies are too variable to be a reliable predictor of disease progression of human type 1 diabetes

Abstract

Objectives: The detection of a peripheral immune cell signature that specifically reflects autoimmunity in type 1 diabetes would enable the prediction and staging of disease on an individual basis. However, defining such a signature is technically challenging. Reliable interpretation of immune cell-related biomarkers depends on their inherent variability and, to understand this variability, longitudinal analyses are required. Methods: We performed a longitudinal observational study in which 40 individuals with elevated genetic risk of type 1 diabetes and persistent islet autoantibodies provided a blood sample every 4–6 weeks for > 1 year. Results: Peripheral immune cell composition (T cells, NK cells and monocytes) was assessed using well-validated flow cytometry panels and demonstrated that, while non-antigen-specific immune cell subsets were stable over time, autoantigen-reactive T-cell frequencies were highly variable in and between individuals. Neither the frequency nor phenotype of non-antigen-specific subsets or autoreactive CD8+ T cells associated with clinical onset of T1D. Conclusion: The findings from the Type 1 Diabetes Longitudinal BIomarker Trial underscore the inherent challenge of evaluating changes in peripheral immune cell populations as surrogates of organ-specific disease activity. The variability of peripheral antigen-specific T cells precludes their use as a prognostic marker and clearly demonstrates that a reliable prognostic cell signature remains elusive.