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

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.